Expert Opinion on Therapeutic Patents

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O-GlcNAcase inhibitors as potential therapeutics

for the treatment of Alzheimer’s disease and
related tauopathies: analysis of the patent
literature

Jose M. Bartolomé-Nebreda, Andrés A. Trabanco, Adriana Ingrid Velter &

Peter Buijnsters

To cite this article: Jose M. Bartolomé-Nebreda, Andrés A. Trabanco, Adriana Ingrid Velter &
Peter Buijnsters (2021): O-GlcNAcase inhibitors as potential therapeutics for the treatment of
Alzheimer’s disease and related tauopathies: analysis of the patent literature, Expert Opinion on
Therapeutic Patents, DOI: 10.1080/13543776.2021.1947242

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Published online: 08 Jul 2021.

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EXPERT OPINION ON THERAPEUTIC PATENTS
https://doi.org/10.1080/13543776.2021.1947242

REVIEW

O-GlcNAcase inhibitors as potential therapeutics for the treatment of Alzheimer’s

disease and related tauopathies: analysis of the patent literature
Jose M. Bartolomé-Nebredaa, Andrés A. Trabancoa, Adriana Ingrid Velterb and Peter Buijnstersb
a
A Division of Janssen-Cilag SA, Discovery Chemistry Department, Discovery, Product Development & Supply, Janssen Research and Development,
Toledo, Spain; bA Division of Janssen Pharmaceutica NV, Discovery Chemistry Department, Discovery, Product Development & Supply, Janssen
Research and Development, Beerse, Belgium

ABSTRACT ARTICLE HISTORY

Introduction: O-GlcNAcylation is a highly abundant post-translational modification of multiple proteins, Received 05 March 2021
including the microtubule-binding protein tau, governed by just two enzymes’ concerted action Accepted 21 June 2021
O-GlcNAc transferase OGT and the hydrolase OGA. It is an approach to reduce abnormal tau hyperpho­
KEYWORDS
sphorylation and aggregation in Alzheimer’s disease (AD) and related tauopathies based on the ability
O-GlcNAcase; OGA; tau;
of O-GlcNAcylation competing with tau phosphorylation, thus minimizing aggregation. The preclinical Alzheimer’s disease;
validation confirmed OGA inhibitors’ efficacy in different transgenic tau mice models. Only three other tauopathies
OGA inhibitors have advanced into clinical trials thus far.
Areas covered: 2008–2020 patent literature on OGA inhibitors.
Expert opinion: Neurodegenerative disorders and AD specifically represent an enormous challenge
since no effective treatments are available. Promising preclinical data has prompted considerable
interest in searching for OGA inhibitors as a potential treatment for neurodegenerative disorders.
Efforts from different companies have yielded a diverse set of chemotypes. OGA is a highly ubiquitous
enzyme with many client proteins, generated data confirms a promising benign profile for OGA
inhibition in healthy volunteers. Additionally, OGA PET tracers’ existence will be critical for proper
dose selection for future PoC Phase II studies, which will proof the true potential of OGA inhibition for
the treatment of AD and other tauopathies.

1. Introduction preparations in 1994 [27]. Then in 1998, it was identified as

antigen five expressed by meningiomas (MGEA5) [28]. Full-
O-GlcNAcylation is a post-translational modification (PTM),
length OGA is a 103 kDa ubiquitously expressed enzyme. It
described for the first time by Torres and Hart in 1984 [1,2].
is soluble and highly conserved in eukaryotes with more than
It consists of the covalent connection of a single sugar
4000 client proteins [29]. Two different isoforms of OGA have
residue, O-linked β-N-acetyl glucosamine (O-GlcNAc), onto
been described so far [30]: long OGA, present in the nucleus
serine and threonine side-chain hydroxyl moieties of
and the cytoplasm, and a shorter isoform (sOGA) mainly found
nuclear, cytoplasmic and, to a lesser extent, mitochondrial
in the nucleus [31]. The catalytic activity of OGA is in the
proteins [3–5]. This PTM is implicated in regulating several
N-terminal part. It belongs to the glycoside hydrolase family
vital cellular processes: gene regulation [6], signal transduc­
84 (GH84) [29]. The C-terminus contains a putative histone
tion [7,8], cell cycle management [9] or proteasomal degra­
acetyltransferase (HAT) domain connected through an intrin­
dation[10]. Dysregulation in O-GlcNAcylation is associated
sically disordered stalk region [32,33]. OGA catalyzes the
with diseases, i.e. insulin resistance [11,12], obesity [13],
hydrolytic cleavage of O-GlcNAc residues from client proteins
diabetes [14,15], cardiovascular diseases [16], cancer [17,18]
through a two-step mechanism. The substrate acetamido
and neurodegeneration [19,20].
group [34] assists and acts as an intramolecular nucleophile
Akin to other PTMs, such as phosphorylation,
attacking the anomeric position. This process involves the
O-GlcNAcylation is a non-canonical, highly dynamic and rever­
participation of two aspartic (Asp) acid residues in the active
sible process [21,22]. The two concerted actions of the
site (Asp 174 and Asp175) and takes place through the forma­
enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA)
tion of a bicyclic oxazolidine-containing intermediate [35].
are responsible for O-GlcNAcylation homeostasis. OGT installs
The first OGA inhibitor used for in vitro studies was the
the O-GlcNAc residue on proteins using UDP-GlcNAc as
natural product streptozotocin (STZ, 1, Figure 2) [36,37]. STZ is
a donor. [23–25] OGA, a hydrolase, is accountable for its
a modest micromolar inhibitor in vitro with limited applicabil­
hydrolytic removal (Figure 1). OGA, initially described as hex­
ity due to structure-related toxicities unrelated to its ability to
osaminidase C [26], was isolated and purified from spleen
inhibit OGA [38]. PUGNAc [39] (2, Figure 2) is a significantly

CONTACT Peter Buijnsters pbuijnst@its.jnj.com Discovery Chemistry; Discovery, Product Development & Supply, Janssen Research and Development,
Turnhoutseweg 30, 2340 Beerse, Belgium
© 2021 Informa UK Limited, trading as Taylor & Francis Group
 2 J. M. BARTOLOMÉ-NEBREDA ET AL.
Article highlights
● O-GlcNAcylation is a highly abundant post-translational modification of
multiple proteins. It includes the concerted action of O-GlcNAc transfer­
ase OGT and the hydrolase OGA.
● In Alzheimer’s disease (AD) and related tauopathies, tau gets hyperpho­
sphorylated and aggregates into neurofibrillary tangles. The extent, the
spreading pattern and the concentration of neurofibrillary tangles cor­
relate with neurodegeneration severity. In vitro, increased
O-GlcNAcylation reduces tau aggregation’s extent and speed, and
O-GlcNAcylation can compete with phosphorylation.
● Extensive preclinical validation, using relevant tau transgenic models,
has confirmed robust in vivo efficacy for the highly potent and brain
penetrant OGA tool compound Thiamet G.
● OGA inhibition has emerged as a novel potential therapeutic target for
treating AD and related neurodegenerative diseases.
● Three OGA inhibitors have entered clinical trials: MK-8719 from Merck/
Alectos, ASN-120,290 from Asceneuron S.A. and LY-3,372,689 from Eli
Lilly.
● Released data suggests a benign side effect profile for MK-8719 and
ASN-120,290 and confirmed target engagement in the brain for MK-
8719.
● Phase II PoC studies are still pending to undoubtedly support the great
promises that OGA inhibition holds for treating AD and related
tauopathies.
This box summarizes key points contained in the article.
more potent in vitro inhibitor than STZ. However, its limited
selectivity versus lysosomal hexosaminidases [35] has also
hampered its wider use. Off-target inhibition of the lysosomal
hexosaminidases is undesirable due to the association of these
enzymes with the lysosomal storage disorders Tay-Sachs and
Sandhoff diseases. Figure 2 depicts a series of fused thiazoline-
containing OGA inhibitors designed and inspired by oxazoline
intermediate 3. NAG-Thiazoline [40] (4, Figure 2), the first
member of the series, is a potent OGA inhibitor but lacks
adequate selectivity versus lysosomal hexosaminidases [35].
The introduction of larger substituents on the thiazoline core
resulted in a significantly improved selectivity in NButGT [41]
(5, Figure 2), especially in Thiamet G [42] (6, Figure 2). Thiamet
G is a highly potent and selective inhibitor that additionally
possesses the ability to penetrate the blood-brain barrier and
is currently the most widely used OGA tool compound.
Figure 2 depicts a structurally unrelated OGA inhibitor,
GlcNAcstatin C [43] (7), a highly potent and selective tetrahy­
dro-imidazopyridine-containing, picomolar inhibitor. The imi­
dazopyridine core of GlcNAcstatin C is proposed to act as
Figure 1. Schematic representation of the O-GlcNAcylation cycle.
a transition state mimic of the planar oxocarbenium ion-like
OGA transition state, which could explain this compound’s
high potency[43]. Noteworthy is the publication of iminocycli­
tol derivative 8, a potent, orally available and brain-penetrant
OGA-inhibitor. [44]
X-ray crystallography aided the identification and optimiza­
tion of various prototypical OGA-inhibitors mentioned above.
However, they used different bacterial OGA orthologs,
whereas human OGA crystallography remained elusive until
very recently. Three independent laboratories reported, almost
simultaneously, X-ray-derived structures of other human OGA
constructs complexed with different inhibitors, including
Thiamet G [45–47]. This will undoubtedly spur on the rational
design of novel classes of inhibitors.
OGT and OGA are expressed ubiquitously in the human body.
One of the highest expressing areas for both enzymes is the brain
[4,28] especially hippocampal and the cortical regions [48–50]. In
addition, several brain-specific proteins are O-GlcNAcylated [51],
thereby suggesting a prominent relevant role for GlcNAcylation in
regulating multiple brain processes[52]. The hexosaminidase path­
way (HBP, Figure 1) [53]converts 3–5% of the body glucose to UDP-
GlcNAc. Moreover, dysregulation of brain glucose metabolism by
decreasing O-GlcNAcylation of proteins might play a role in the
pathogenesis of neurodegenerative diseases such as AD[54]..
Moreover, the formation of neurofibrillary tangles (NFTs) as
a result of abnormal hyperphosphorylation and aggregation of tau-
proteins is one of AD’s main hallmarks. Recent longitudinal studies
in AD patients confirmed that tau aggregation, spreading pattern,
and concentration of NFTs correlate with neurodegeneration, brain
atrophy, and cognitive symptom evolution, suggesting a pivotal
role for tau in disease progression [55,56]. Aggregates of hyperpho­
sphorylated tau are also a common feature of other neurodegen­
erative diseases, collectively termed tauopathies. They comprise
progressive supranuclear palsy (PSP), frontotemporal dementia
(FD) or corticobasal syndrome (CBS), among others [57]. Tau is
one of the client proteins of OGA[58]. Postmortem studies of AD
brain extracts revealed a reduction of O-GlcNAcylated tau levels
and an almost entire lack of O-GlcNAcylation in aggregates.
[19,55,59] In a related way, in vitro studies have shown how
O-GlcNAcylation reduces tau aggregation’s degree and speed in
cells [60,61].
Phosphorylation and O-GlcNAcylation occur on identical
residues on client proteins suggesting a reciprocal interplay
between them. Thus, O-GlcNAcylation could directly compete
with phosphorylation on the identical residues and indirectly
 EXPERT OPINION ON THERAPEUTIC PATENTS 3

affect neighboring or proximal sites [62,63]. This evidence

supports a potential role for the upregulation of tau
O-GlcNAcylation via OGA inhibition with small molecules for
the possible treatment of AD and related tauopathies[64].
Suitable OGA inhibitor tool compounds played an essential
role in the preclinical validation of the hypothesis, as men­
tioned above. Sub-chronic administration of Thiamet G [43] in
rodents revealed that OGA inhibition is well-tolerated.
Prolonged OGA inhibition in transgenic mice expressing pro- Figure 3. Structure of the Merck/Alectos clinical asset MK-8719 and the Eli Lilly
aggregation tau-mutants (JNPL3 [65,66] and Tg4510 [67–70]) PET tracer [18F]-LSN3316612.
showed an increase in tau O-GlcNAcylation, decreasing tau
aggregation and NFTs. In P301L transgenic mice, it reduced
Treatment with MK-8719 increased the O-GlcNAc level in per­
the severity of breathing defects and enhanced survival [71].
ipheral blood mononuclear cells (PBMCs) and displacement of
Nurtured by these promising results, several pharmaceutical
[18F]-MK-8553, a positron emission tomography (PET) ligand of
companies have embarked on drug discovery programs to
undisclosed structure, in the brain. Asceneuron S.A. has also
identify OGA inhibitors that could have the potential to pro­
reported phase I data on ASN-120,290 (formerly ASN-561); its
gress into clinical trials to confirm in humans the therapeutic
molecular structure is unknown, and the compound is being
potential of this approach for the treatment of AD and related
developed for PSP treatment. Sub-chronic administration of
tauopathies [72]. A close analogue of Thiamet G, MK-8719,
ASN-120,290 to P301S mice proved to be well tolerated and
compound 9 (Figure 3) has an improved brain penetration
increased tau O-GlcNAcylation and significantly reduced
and a favorable preclinical toxicological profile. Therefore,
abnormally hyperphosphorylated tau [76,77]. In the clinic,
Merck/Alectos have moved MK-8719 [73] (9, Figure 3) into
ASN-120,290 was safe and taken by healthy young and elderly
phase I clinical trials for PSP treatment. Thus, single ascending
volunteers following single oral doses up to 1000 mg and after
doses (SAD) of MK-8719 up to 1200 mg have shown good
multiple oral doses up to 500 mg BID. To support dose selec­
pharmacokinetics, and the compound was safe and well-
tion for PSP efficacy trials, Asceneuron S.A. has also reported
tolerated with no noticeable adverse effects [74,75]. In vivo,
the start of an additional clinical trial aimed to evaluate target
target engagement was confirmed in blood and the brain.
engagement of ASN120,290 in the brain using a proprietary

Figure 2. Structures of some prototypical OGA inhibitor tool compounds.

4 J. M. BARTOLOMÉ-NEBREDA ET AL.

PET ligand of undisclosed structure [78]. Finally, Eli Lilly also
claims in its pipeline to have both an OGA inhibitor (LY-
3,372,689) [79] of an unknown structure [80] as well as a PET
ligand ([18F]-LSN3316612) [81] undergoing Phase 1 clinical
trials for AD. However, no data has been released yet.
Following the high promise as potential therapeutic agents held
by OGA inhibitors, supported by the extensive preclinical validation
described above, this review will summarize the existing OGA small
molecule patent landscape focusing onAD and related tauopathies.
2. Patent review of OGA inhibitors
2.1. Simon Fraser University/Alectos Therapeutics Inc.
and Merck, Sharp & Dohme Corp
Simon Fraser University first, followed by Alectos Therapeutics
(a spin-out company from Simon Fraser University) in a license
and research collaboration agreement with Merck Sharp &
Dohme Inc., published multiple patent applications around
several chemotypes between 2008 and 2014. Among those,
they published six patent applications disclosing substituted
octahydroindolizines, piperidines and pyrrolidines. The first
application from 2010 described 51 compounds, all compris­
ing a (1S,6S,7 R,8 R,8aR)-6-aminooctahydroindolizine-1,7,8-triol
scaffold[82]. Figure 4 depicts some specific derivatives (11–14)
from the patent application. It contains substituted amines,
amides and ureas, of which the R-groups are linear, substi­
tuted small alkyl or alkenyl radicals. Simultaneously, the patent
application disclosed three unsubstituted benzylic derivatives,
and it revealed hOGA enzymatic activity for compound 11
only.
The next case, also from 2010, disclosed 30 2-(amino­
methyl)-pyrrolidine-3,4-diol derivatives defined by the

Figure 4. Representative aminooctahydroindolizine OGA inhibitors from Simon Fraser University.

Figure 5. Representative substituted pyrrolidine OGA inhibitors from Simon Fraser University.

Figure 6. Representative substituted pyrrolidine OGA inhibitors from Simon Fraser University, Alectos Therapeutics and Merck Sharp & Dohme.
 EXPERT OPINION ON THERAPEUTIC PATENTS 5

Figure 7. Representative substituted pyrrolidine OGA inhibitors from Simon Fraser University, Alectos Therapeutics and Merck Sharp & Dohme.

Figure 8. Representative substituted piperidine-3-carboxamide OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.

Figure 9. Representative substituted piperidine-2-carboxamide OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.
6 J. M. BARTOLOMÉ-NEBREDA ET AL.
Markush formula depicted in Figure 5[83]. It describes mainly
acetamides such as compound 15 with 0.85 µM enzymatic
activity for hOGA. Other variations include various alkyl groups
on the pyrrolidine N1 atom, e.g. 16–19, and different groups
at C5 position such as compounds 20 and 21.
In 2014, two patent applications, WO032185 [84] and
WO032188[85], described various substituted pyrrolidine ana­
logues. The first publication disclosed 21 substituted pyrroli­
dines, and Figure 6 depicts that all the compounds in that
document have no substituents at the C2 position. The pyrro­
lidines contain F-atoms at the C4-atom and the C5 methylene
group (compounds 22–24). Most likely, the presence of the
F-atoms helps modulate the basicity of the pyrrolidine
N-atom. Most of the molecules comprise a 3-carbon tether
that links a (hetero)aromatic group to the pyrrolidine
(Figure 6). Furthermore, most compounds include an aceta­
mide or a propionamide at the N3-atom. However, the docu­
ment revealed biological activity for three compounds 27–29
only.
Figure 10. Representative tetrahydro-4 H-cyclopenta[d]oxazole and thiazole-
4,5-diol OGA inhibitors from Simon Fraser University.
Figure 11. Representative hexahydrobenzo[d]oxazole-4,5-diol OGA inhibitors from Simon Fraser University, Alectos Therapeutics and Merck Sharp & Dohme.
The subsequent patent application (WO032188) reported
more chemical diversity (Figure 7). The exemplified com­
pounds, however, differ in the position the amide is attached
to the 2-position of the pyrrolidine core, i.e. CH2N(CO)alkyl or
(CH2)C(O)N-alkyl.
Figure 7 depicts several representative examples that
demonstrate this difference (30–35). The most promising bio­
logical activity resides in compounds with the three-carbon
tether when comparing close analogues (33, 34, 38). This
patent publication reveals apart from hOGA biological data
also intrinsic permeability for selected molecules (compounds
31 and 32). Interestingly, the chirality has a marked influence
on the pharmacological activity, i.e. the 3S-hydroxy derivative
(39) is approximately seven times more active than the
3 R analogue (33). Again, several examples have F-atoms
installed at different positions in the products like in the
previous application; however, without biological activity.
The subsequent two patent applications disclosed piperi­
dine derivatives. These compounds revealed a similar substi­
tution pattern, and the various groups decorating them are
very similar to the pyrrolidine derivatives. In WO032187, the
C2-atom is not substituted, and the R-groups have
a comparable scope as the corresponding pyrrolidines
(WO032185). Compound 40 (Figure 8) has an inhibitory activ­
ity of 2578 nM against hOGA [86].
The 2-substituted piperidine derivatives described in
WO032184 resemble the pyrrolidine analogues of WO032187.
Albeit, all the 56 exemplified compounds are 2-methyl or
2-ethylcarboxamides. Figure 9 shows some representative
examples, and derivative 41 has a remarkable difference in
biological activity compared to molecule 42, 165 nM versus
 EXPERT OPINION ON THERAPEUTIC PATENTS 7

Figure 12. Representative 2-(dimethylamino)-1-hydroxyethyl-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazole-4,5-diol OGA inhibitors from Alectos Therapeutics and Merck
Sharp & Dohme.

3297 nM, respectively. Furthermore, adding more lipophilicity
as in compounds 43–45 results in interesting SAR. Moreover, it
resulted in a single-digit nanomolar inhibitor 43, but it does
not improve the ligand efficiency (LE) compared to compound
41, i.e. LE amounts to 0.62 and 0.37, respectively [87].
Eight patent applications revealed Thiamet G (6) analogues.
They described differences in the central core scaffold: (1) the
size of the two interconnected rings, (2) the nature of the
heteroaromatic 5-membered moiety and (3) the various
(cyclo)alkyl substituents. The first document (WO012107) [88]
described 21 exemplified compounds that possess instead of
a tetrahydro-5 H-pyrano[3,2-d]thiazole moiety (Thiatmet G) or
a tetrahydro-4 H-cyclopenta[d]oxazole core a tetrahydro-
4 H-cyclopenta[d]thiazole (Figure 10) comprising alkyl,
branched alkyl, cycloalkyl, aryl or heteroaryl groups. Still, in
most cases, this includes N(Me)2, and biological data is
reported for one molecule (46) only.
The next application disclosed (WO140640) [89] com­
pounds that comprise hexahydrobenzo[d]thiazole and hex­
ahydrobenzo[d]oxazole derivatives (33 compounds), in
analogy to the previous document, replacing the O-atom
of the pyrane ring of Thiamet G with a carbon atom.
Figure 11 depicts some exciting examples. Interestingly,
the synthesized examples in this document reveal different
substituents than the previous document, e.g. 4-methoxy­
benzylamino, azetidin-1-yl (52), mono (54), di, or

Figure 13. Representative 6-substituted 2-(azetidin-1-yl)-4-fluoro-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol OGA inhibitors from Alectos Therapeutics and Merck
Sharp & Dohme.

Figure 14. Representative 2-substituted tetrahydro-3aH-pyrano[3,2-d]thiazole OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.
8 J. M. BARTOLOMÉ-NEBREDA ET AL.

Figure 15. Representative substituted tetrahydro-3aH-pyrano[3,2-d]thiazole OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.

trifluoroethylamino, methyl, ethyl compared to the last pub­ The thiazole ring’s inversion has a marked effect on the
lication. The enzymatic activity of the compounds 48, 50, enzymatic activity, Ki 0.5 nM (51, 3aR/7aS) versus 484 nM
51, and 53 against hOGA is in the sub-nanomolar range.

Figure 16. Representative substituted tetrahydro-3aH-pyrano[3,2-d]thiazole OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.

(52: 3aS, 7aR), which appears a crucial feature of these
derivatives.
The inventors explored this specific chemotype in the fol­
lowing two applications [90,91]. Figure 12 shows representa­
tive examples which mainly differ at the 6-position of the
hexahydrobenzo[d]oxazole or thiazole ring system. The (6S)
configuration of the hydroxyethyl group is the preferred one,
i.e. the primary hOGA potency increased 10- or 18-fold for
compounds 56 and 58 and 57 and 55, respectively.
Inversion of the 7a and the 3a position from 3aS/7aS to 3aR/
7aR results in a 1680-fold decrease in primary potency, 57
versus 59.
Figure 13 depicts representative azetidine-1-yl derivatives
(60–63) of the same scaffold; however, they do not meet the
previous publication’s activity. This document revealed the
Figure 17. Representative close analogues of Thiamet G as OGA inhibitors from
Alectos Therapeutics and Merck Sharp & Dohme.
Figure 18. Representative substituted tetrahydro-3aH-pyrano[3,2-d]thiazole OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.
EXPERT OPINION ON THERAPEUTIC PATENTS 9
structure of 32 molecules and the biological data and intrinsic
permeability of seven compounds. Introducing fluorine atoms
at different positions on the molecule reduces the topological
polar surface area (TPSA). In this way, the inventors envisaged
enhancing the intrinsic and blood-brain permeability,
a recurring theme in the patent applications from Alectos
Therapeutics/Merck Sharp and Dohme.
Alectos replaced the six-membered cyclohexane ring with
a tetrahydropyran moiety (WO061927, WO061971 and
WO129651) [92–94]. They disclosed 21 substituted tetrahy­
dro-3aH-pyrano[3,2-d]thiazoles, and Figure 14 reveals various
exemplified molecules. Enlarging the ring size and adding
(polar) substituents on the cyclic group at the two-position
of the thiazole ring resulted in a decrease in inhibitory potency
against hOGA viz. molecules 64–68.
Figure 15 depicts a further elaboration of this tetrahydro-
3aH-pyrano[3,2-d]thiazoles scaffold at the two and the pen­
dant five positions.
The application disclosed the synthesis of 57 compounds
and the biological data of 18 derivatives. The inhibitory activ­
ity against hOGA is in the 0.6–10 nM range, and the various
groups at the pendant five-position have little effect on the
potency, which is clear from Figure 15 (69–74). The most
active compound is derivative 71 (0.6 nM, LE = 0.67).
Changing the group’s nature at position five of the scaffold
into a carbamate did not significantly improve the in vitro
biological activity; compounds 75 and 76. However, the car­
bamate moiety negatively impacted the cellular activity by
almost twenty-fold versus the in vitro activity.
In another application [95], the same scaffold is explored
further by modifying the pyrane ring, i.e. omitting various
hydroxyl functionalities and adding fluorine atoms at different
positions and with specific configurations. Figure 16 shows
some representative examples, and noteworthy are the exam­
ples that possess improved intrinsic permeability resulting in
10 J. M. BARTOLOMÉ-NEBREDA ET AL.
improved cellular activity. The omission of hydroxyl function­
alities, the addition of Me-groups, and the replacement of
hydroxy groups with fluorine atoms result in improved proper­
ties. Primary activity data enhances by removing the ability of
H-bond donating capability by adding an alkyl group. This,
however, did not increase the cell-based activity viz. com­
pounds 77 and 79. Compounds that lack the 7-OH group
are less potent than the corresponding substituted ones,
either with a 7-OH or a 7-F moiety. Replacing hydroxyl groups
with F-atoms reduces TPSA, enhances the intrinsic permeabil­
ity, and improves the cellular activity, e.g. molecules 80–82
with molecule 82, the most interesting one disclosed in this
patent application. Noteworthy is the configurational impact
of the six-position at the tetrahydropyran ring. The (6S)-OH is
about 30-fold more active than the (6 R)-OH, compare mole­
cule 80 with 83, 5.7 nM and 164 nM, respectively.
Figure 17 depicts four close analogues of Thiamet G. Subtle
changes in the stereochemical nature of the hydroxyl groups
at the 6- or 7-position had a significant effect on the in vitro
activity. The full stereochemical descriptors and name of
Thiamet G (90, Figure 18) is (3aR,5 R,6S,7 R,7aR)-2-(ethyla­
mino)-5-(hydroxymethyl)-3a,6,7,7a-tetrahydro-5 H-pyrano
Figure 19. Representative substituted tetrahydro-3aH-pyrano[3,2-d]thiazole OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.
[3,2-d]thiazole-6,7-diol. Changes in the configuration of
a single hydroxyl from 6S to 6 R while keeping the other
stereo centers constant, resulted in a decrease of activity,
albeit compound 86 is not a matched pair of Thiamet
G. Then, adding another methyl group to the amino group
increased the enzymatic activity 8.5-fold viz. compound 86;
243,3 nM versus compound 87; 28.6 nM.
The in vitro activity of the matched pair of Thiamet G,
molecule 88, which has a 7S instead of 7 R configuration,
decreased about 10-fold. Remarkably, changing the
6 R,7 R to 6S, 7S like in compound 89, a direct analogue of
86, resulted in the best hOGA enzymatic activity of 0.7 nM in
this publication[96].
They disclosed in another application [97] molecules with
a sulfur atom instead of oxygen or a carbon atom, i.e. tetra­
hydro-5 H-thiopyrano[3,2-d]thiazole ring system. Figure 18
depicts representative examples and the biological data of 6
compounds. Incorporation of a sulfur atom resulted in an
increase of the TPSA compared to an oxygen atom; however,
the intrinsic permeability is the reverse order viz. molecule 92;
3.7 × 10−6 cm/s versus molecule 90 (Thiamet G); <1.0x10−6
cm/s. The cellular activity, however, is correlating with the
 EXPERT OPINION ON THERAPEUTIC PATENTS 11

Figure 20. Representative substituted tetrahydro-3aH-pyrano[3,2-d]thiazole OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.

Figure 21. Representative substituted tetrahydro-3aH-pyrano[3,2-d]thiazole OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.

Figure 22. Representative substituted tetrahydro-3aH-pyrano[3,2-d]thiazole OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.
12 J. M. BARTOLOMÉ-NEBREDA ET AL.
primary potency; 90, Ki (hOGA) = 0.4 nM, EC50 = 13 nM versus
92, Ki(hOGA) = 3.0 nM, EC50 = 139 nM, approximately ten-fold
difference.
The following two applications disclosed tetrahydro-
5 H-pyrano[3,2-d]thiazole derivatives, and Figure 19 depicts
various representative examples [98,99]. The R1 and R2 groups
comprise small alkylic moieties such as Me, Et, Pr, cBu, cPent,
methoxy(methyl)amino and cyclopropyl methyl groups. These
derivatives possess excellent in vitro enzymatic activity in the
sub-nanomolar range, i.e. 0.12–16.3 nM and the SAR among
the different sub-series is relatively flat. The in vitro potency
correlates well with the cellular activity with a 4- to 30-fold
difference in many examples. An exception is compound 101,
with a Ki of 0.82 nM and an EC50 of 62.7 nM in the cell-based
assay.
Another publication of Alectos Therapeutics and Merck
Sharp & Dohme overlapped with the previous applications,
albeit with some slightly different derivatives with various
fluorine-containing groups, and Figure 20 depicts some fasci­
nating examples[100]. These very potent inhibitors in the
enzymatic hOGA assay did not translate in high potency in
Figure 23. Representative radiolabeled substituted tetrahydro-3aH-pyrano[3,2-d]thiazole OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.
the cell-based assay than some of the compounds illustrated
in Figure 19.
Another application revealed an exploration of the
2-amino group viz. small alkylic groups, amides and ureas
[101]. The publication described the synthesis of thirty-one
derivatives and the biological activity of 8 examples.
Figure 21 depicts representative molecules, and the
in vitro activity is lower than other derivatives from the
same scaffold (114–116).
In another application, WO000084, the Alectos and Merck
Sharp & Dohme researchers disclosed 80 compounds, of
which 17 derivatives revealed interesting SAR. Changing
the stereochemical nature from (7 R) to (7S) improved the
in vitro potency moderately; 3.6-fold, 1,1 nM versus 0.3 nM,
molecule 117 versus molecule 118, respectively (Figure 22).
The in vitro activity decreased 886-fold when the hydro­
xyethyl group’s stereochemistry inverted from (1S) to (2 R);
compare compounds 117 to 119; 0.3 nM versus 266 nM,
respectively. Moreover, changing the hydroxyl group from
(6 R) to (6S) at the tetrahydro-5 H-pyrano[3,2-d]thiazole core
decreased the activity 510-fold; viz. compounds 113 to 120,
 EXPERT OPINION ON THERAPEUTIC PATENTS 13

Figure 24. Representative substituted tetrahydro-3aH-pyrano[3,2-d]thiazole OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.

Figure 25. Representative substituted tetrahydro-3aH-pyrano[3,2-d]thiazole OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.
14 J. M. BARTOLOMÉ-NEBREDA ET AL.
1.1 nM versus 562 nM, respectively. The omission of an
F atom at the 7-position resulted in a 23-fold decrease of
activity, viz. compound 122 compared to derivative 117. In
addition to this, removing one hydroxyl group at the 1-posi­
tion also diminished the activity 140-fold, i.e. compound
117 versus derivative 121 (Figure 22).
Two applications, WO166654 and WO169576, revealed
O-Glc-NAcase imaging agents labeled with [101]C isotopes
[102,103]. They disclosed compounds that possess elaborate
substitution patterns on the hydroxyl group with linear alkyl
groups or (hetero)aromatic moieties. Substitution patterns
encompass fluorine atoms, small cycloalkyl groups or more
polar moieties, whereas the aromatic groups possess small
substituents, at different positions, such as methyl, fluorine,
methoxy. Both applications do not disclose the PET tracers’
data (compounds 123–125). The corresponding non-
radiolabeled compounds 126–128 combine moderate to
good in vitro activity and cellular potency with an intrinsic
permeability exceeding 20 × 10−6 cm/s (Figure 23).
Figure 26. Representative substituted tetrahydro-3aH-pyrano[3,2-d]thiazole OGA inhibitors from Simon Fraser University.
Figure 27. Representative substituted piperidin-1-yl-methyl-(thiazol-2-yl)acetamide OGA inhibitors from Alectos Therapeutics and Merck Sharp & Dohme.
However, using the data from the application WO169576,
different compounds could have been selected because deri­
vatives 129–131 (Figure 23) combine the best values for the
in vitro, cellular, and permeability data reason for the initial
selection remains, therefore, elusive.
In February 2014, Alectos published an application contain­
ing Thiamet G derivatives revealing remarkable differences
between diastereomers [104]. The chirality of the flexible
group attached at the sugar moiety has a significant effect
on the enzymatic hOGA activity. Figure 24 depicts representa­
tive examples.
Inversion of the chirality increased the enzymatic activity
significantly. The difference between the diastereomeric
mono-methyl derivatives is smaller than for the dimethyl
ones; compound 134 versus 135, and derivatives 136/137
versus 138/139 (Figure 24). Interestingly, the additional
methyl group decreased the PgP efflux ratio by about 7-fold.
The intrinsic permeability was for the matched pairs within
a similar range; changing the PSA was in this case, decisive for
less efflux; compare compound 134 (Papp = 18.8x10−6 cm/s,

Figure 28. The resemblance of piperidin-1-yl-methyl-(thiazol-2-yl)acetamide OGA inhibitor from Alectos Therapeutics and Merck Sharp & Dohme and the PET-tracer
of Eli Lilly.
PgP efflux = 21) to 137 (Papp = 28x10−6 cm/s, PgP
efflux = 3.5).
This application also revealed compounds possessing smal­
ler groups, such as depicted in Figure 25. These derivatives
displayed noteworthy behavior in the enzymatic activity upon
small molecular changes. Changing the methyl group to an
ethyl one decreased the primary activity 30-fold (compounds
140 versus 141). Linear moieties such as an alkyne of a cyano
functionality resulted in less active compounds, i.e. 837 nM
and 601 nM for derivatives 142 and 144. Interestingly, chan­
ging the CN-group into a CH2CN group decreased the activity
more than 550-fold, albeit no matched pairs, 1.08 nM versus
601 nM, compounds 143 and 144, respectively. Installing
Figure 29. Representative Thiamet G analogues from Merck GMBH.
EXPERT OPINION ON THERAPEUTIC PATENTS 15
secondary and tertiary amides at the same position resulted
in inactive compounds.
Figure 26 represents the same central scaffold’s continua­
tion, namely, the tetrahydro-5 H-pyrano[3,2-d]thiazole core.
The application disclosed 97 examples, out of which three
have biological data (compounds 145–148)[105]. However,
the focus is on the in vivo evaluation of two compounds
Thiamet G (NAG-AE) and NAG-Bt (Figure 26). Increasing
doses of NAG-Bt via intravenous (one time 0–250 mg/kg) tail
vein injection or oral administration (100 mg/kg/day for five
days) elevated O-GlcNAc levels in the brain and muscle,
respectively. IV administration of 50 mg/kg NAG-EA increased
O-GlcNAc levels in cardiac tissue.
16 J. M. BARTOLOMÉ-NEBREDA ET AL.

Furthermore, NAG-Bt and Thiamet G blocked phosphoryla­
tion sites which are involved in the toxic self-assembly of tau.
Moreover, both compounds reduced neurofibrillary tangle for­
mation in transgenic P301LJNPL3 mice and the tau phosphor­
ylation levels, albeit through different dosing regimens and
doses; NAG-Bt at 100 mg/kg/day via food (week 1–15) and
then 1000 mg/kg/day via drinking water (week 16–32);
Thiamet G at 500 mg/kg/day via drinking water (week 16–
32). An eight to nine months repeat-dose toxicology in vivo
evaluation of both NAG-Bt and Thiamet G revealed that both
compounds have a suitable safety profile for the studies
performed.
In WO106254 Alectos Therapeutics and Merck Sharp &
Dohme disclosed compounds based on an N-(thiazol-2-yl)acet­
amide scaffold[106]. The publication revealed the enzymatic
hOGA data of 54 compounds and interesting SAR. Figure 27
depicts some compelling examples of this class of hOGA
inhibitors. Compounds 148–155 reflect the effect on the enzy­
matic activity of the spatial orientation of the double bond to
the chiral center at the piperidine. The absolute S,

Figure 30. Representative N-substituted phenylpiperidine OGA inhibitors from Merck GMBH.

Figure 31. Representative 4-substituted piperidin-1-yl-methyl-(thiazol-2-yl)acetamide OGA inhibitors from Merck GMBH.
 EXPERT OPINION ON THERAPEUTIC PATENTS 17

Z-configuration resulted in the highest primary activity for
multiple compounds disclosed in this publication.
This document revealed another exciting compound, and
Figure 28 shows the similarity of this compound 156 and the
Eli Lily PET-tracer [18F]-LSN3316612.
2.2. Merck GMBH
In February 2013, scientists at Merck Patent GMBH published
an application that disclosed 105 Thiamet G analogues as
hOGA inhibitors[107]. All the analogues posess the central
pyrano[3,2-d][1,3]thiazole core (Figure 29). They encompass
variations introduced at the 2-amino substituent of the

Figure 32. R of N-4 substituents on the N1-arylpiperazine core from Asceneuron S.A.

Figure 33. Examples of N1 substituents on the N4-(1-arylethyl)-piperazine core from Asceneuron S.A.
18 J. M. BARTOLOMÉ-NEBREDA ET AL.

dihydrothiazole ring, at the hydroxyl substituents and the
5-position of the tetrahydropyranyl ring. This patent reported
the enzymatic and cellular activity of the OGA inhibitors. The
cellular assays utilized rat B35, rat PC-12 and human Sh-SY5Y
cells, expressing endogenous OGA levels. Increases in
O-GlcNAcylated cellular protein levels were measured using
CTD110.3 antibody and determined by the ELISA technique.
Four compounds demonstrated hOGA inhibitory activity
below 100 nM in both enzymatic and cellular assays, e.g.
157, 159, 160 and 161 (Figure 29). All of them contained

Figure 34. Representative dihydrobenzofurane OGA inhibitors from Asceneuron S.A.

Figure 35. Examples of piperazine OGA inhibitors from Asceneuron S.A.


a 2-aminoethyl substituent on the dihydrothiazole ring.
Substituents at the 5- position of the tetrahydropyranyl ring
included chloromethyl (156), 1-hydroxy-3-arylpropyl (158) and
methyltriazolyl analogues, e.g. 159–161. Interestingly, the
more sterically hindered trifluoromethylphenyl ethanol analo­
gue 160 did not show any inhibitory effect in the cellular
assay. Most likely, the topological polar surface area of this
derivative, 150 Å2 for compound 160 vs 130 Å2 for derivative
159, hampered the cellular permeability. In contrast, the
hydroxy substituent at C5 of the tetrahydropyranyl ring of
molecule 158 could be involved in internal H-bonding, thus
displaying a reduced TPSA (119 Å2) and therefore improved
cell permeation.
In 2014, researchers at Merck GMBH filed a second applica­
tion disclosing 4-substituted piperidin-1-yl-methyl-(thiazol-
2-yl)acetamide derivatives as glycosidase inhibitors[108].
A total of 65 compounds were exemplified, out of which 26
analogues revealed hOGA IC50 < 200 nM in the enzymatic
inhibition assay, whereas four analogues demonstrated an
EC50 < 200 nM cell inhibition assay utilizing B35 rat neuroblas­
toma cells. Most examples carried a common piperidine core,
N-substituted by a 5-methylenethiazol-2-acetamide moiety
(Figures 30, 162). Interestingly, methylation of the acetamide
moiety in this compound, or its replacement with an amine or
sulfonamide moiety, derivatives 163–165, lead to a significant
loss of enzymatic activity. Aliphatic substituents at 4-position
of the piperidine core, such as benzyl, phenethyl or cyclohexyl
derivatives 166–168 (Figure 31), were beneficial for OGA inhi­
bitory activity in both assays. The introduction of a quaternary
center at the 4-position of the piperidine core was detrimental
for activity, as illustrated by derivative 169. In this case, it
seemed that steric rather than electronic effects were
Figure 36. Representative piperazine OGA inhibitors from Asceneuron S.A.
EXPERT OPINION ON THERAPEUTIC PATENTS 19
responsible for the loss in potency since 3-F piperidine analo­
gue 170 maintained the hOGA enzymatic activity.
Replacement of the piperidine core by piperazine resulted in
decreased enzymatic and cellular OGA inhibitory activity
(Figures 32, 171).
2.3. Asceneuron S.A
Asceneuron S.A., a spin-off of Merck Serono’s Alzheimer’s drug
discovery portfolio and research group in Switzerland[109],
filed 12 patents, in which they disclosed a variety of 1,4-dis­
ubstituted piperidyl or piperazinyl analogues as glycosidase
inhibitors. Thus, in 2016, Asceneuron S.A. revealed a new ser­
ies of glycosidase inhibitors, most of which featured an N1-aryl
-N4-(1-arylethyl)-piperazine common central scaffold[110]. This
application disclosed 202 compounds, of which 63 demon­
strated potent OGA enzymatic activity, with hOGA IC50
< 50 nM. Of these compounds, the preferred N-4 substitution
seemed to be bicyclic heterocycles, either exclusively aro­
matic, such as quinoxaline (172), or benzothiazole (173), or
containing partially saturated rings such as dihydrobenzofur­
anes, benzoxolane or benzodioxane, as exemplified in
Figure 32, molecules 174–176.
Among the preferred substituents on the piperazine scaf­
fold, selected examples include N1-substituted pyrimidines
(177–179, Figure 33) and pyridines or bicyclic heterocycles,
e.g. tetrahydrothiazolopyridines 180–181.
The publication claimed that the preferred compounds in
this patent, 182–185, depicted in Figure 34, demonstrated
acceptable drug-like properties, such as metabolic stability in
liver microsomes, stability toward oxidation or cellular perme­
ability. Furthermore, these compounds showed high biological
20 J. M. BARTOLOMÉ-NEBREDA ET AL.
Figure 37. Examples of 2,3-dihydrobenzofuran-6-ethylpiperazine OGA inhibitors from Asceneuron S.A.
Figure 38. Representative [1-(benzothiazol-5-yl)ethyl]piperazine OGA inhibitors from Asceneuron S.A.
activity, as determined by the level of OGlcNAcylation of the
total proteins measured in rodent brain extracts.
Later patents from Asceneuron S.A. disclosed additional
analogues of the piperazine derivatives described above
[111]. Thus applications from August 31st, 2017 (WO144633
and WO144639) claimed 287 compounds with the N1-aryl-N4
-(1-arylethyl)-piperazine as their common central scaffold, with
many heterocycles disclosed as N1- and N4- substituents.
From the exemplified analogues, 56 compounds demon­
strated hOGA enzymatic activities at IC50 < 50 nM. Most of
these more potent analogues contained dihydrobenzofuranes
as aromatic N4-substituents, combined with various N1-
piperazine substituents, either monoaryls or bicyclic hetero­
cycles (Figure 34).
Figure 35 depicts other N4-substituents that demonstrated
high potency in the enzymatic hOGA assay, including quinox­
alines, benzothiazoles and naphthyridines, and compounds
186–193. The tetrahydropyrido[4,3-d]pyrimidine analogues
achieved excellent hOGA enzymatic similar to the tetrahy­
drothiazolo[5,4-c]pyridine analogue 182.
Patents filed in the same year disclosed synthetic methods
for the preparation of enantiomerically enriched or pure (S)-
[1-(benzodioxol-5-yl)ethyl]piperazine analogues, with com­
pounds like 173 (Figure 32), 177 (Figure 33), 182 and 185
(Figure 34) being among the specific examples[112]. Other
patents from 2017 claim acid addition salts and polymorphs
of the piperazine analogues discussed above[113].
Furthermore, the physicochemical data for compound 185,
both as free base and acid salts, are provided, such as visual
aqueous solubility, DSC thermogram, X-ray powder diffraction
pattern, Raman spectra, STA thermogram, NMR spectra.
In August 2018, scientists at Asceneuron S.A. disclosed two
additional patents of N,N’-1,4-disubstituted piperazines[114].
The first patent (WO153507) exemplified 21 compounds con­
taining a common 2,3-dihydrobenzofuran-6-ethylpiperazine
substructure substituted with mono-and bicyclic heterocycles

Figure 39. Representative annulated piperidine OGA inhibitors from Asceneuron S.A.
Figure 40. Representative pyrrolidine OGA inhibitors from Asceneuron S.A.
at the N-1 position, among which phenyl, thiadiazoles and
pyrimidines. Nine compounds demonstrated IC50 < 50 nM in
the OGA inhibition assay, and Figure 36 and Figure 37 depicts
representative derivatives. They claimed that introducing
a sulfoximine moiety, as in compound 201, was beneficial
for decreasing the plasma protein binding (PPB) in this series.
The second patent application [115] exemplified 71 sul­
foximine analogues of molecule 201. Apart from the
potency range, the respective free fractions in mouse
plasma were also reported. The exemplified compounds
preserved the piperazinyl central core; however, they
described a broader range of substituents at both N1 and
N4 of the piperazine moiety. These 45 compounds demon­
strated IC50 < 50 nM in the hOGA enzymatic assay. These
included examples such as 202–204 (Figure 38), having
a benzothiazolyl substituent at N4.
EXPERT OPINION ON THERAPEUTIC PATENTS 21
In a more recent patent from February 2019, researchers at
Asceneuron S.A. reported glycosidase inhibitors in which the
central piperidine or piperazine core was annulated into
a bicyclic ring system, demonstrated in Figure 39[116]. The
publication reported potency ranges for 21 compounds out of
162 exemplified analogues only. Of these 21 one molecules,
seven analogues showed hOGA activity between 50–200 nM
in the enzymatic inhibition assay. The 4,5,6,7-tetrahydro-
1 H-pyrazolo[4,3-c]pyridine derivatives demonstrated moder­
ate enzymatic activity, as shown in Figure 39. Benzyl substitu­
ents attached to the central pyrazole core, as in molecule 210,
showed similar a potency range as the compounds having
aromatic substituents directly connected to the pyrazole cen­
tral core (209).
In February 2020, scientists at Asceneuron S.A. disclosed
three different series OGA inhibitors containing pyrrolidines,
22 J. M. BARTOLOMÉ-NEBREDA ET AL.
Figure 41. Representative tetrahydro-benzoazepines OGA inhibitors from Asceneuron S.A.
tetrahydro-benzoazepines and spirocyclic piperidines as
a central core. Thus, a first patent described 465 compounds
having a central pyrrolidine core[117]. The document dis­
closed the enzymatic activity for 94 compounds, of which
four analogues demonstrated IC50 < 50 nM in the hOGA
enzymatic inhibition assay. The majority of the exemplified
compounds contained a pyrrolidine central core with
a 2,3-dihydrobenzo[b][1,4]dioxine moiety or 2,3-dihydrofur­
ane at the 2-position of the pyrrolidine, e.g. 211–216 in
Figure 40. The central core connected various aromatic
groups via a methylene linker, and Figure 40 depicts some
representative examples. The pyrazol-4-yl-pyridine (212,
212) and pyridine-2-yl-pyrimidine derivatives (213) demon­
strated IC50 values below 50 nM. Replacing one aromatic
ring with an aliphatic substituent, as in 214, or fusing the
aromatic ring into a bicyclic heterocycle, as in 215, led to
a decrease in potency. Moreover, changing the orientation
of the aromatic moieties connected to the N atom of the
pyrrolidine ring led to a significant decrease in potency, i.e.
molecule 216.
In a second patent from February 2020, scientists at
Asceneuron S.A. disclosed 2,3,4,5-tetrahydro-1 H-benzo[d]aze­
pine derivatives as potent OGA inhibitors[118]. The document
revealed 363 exemplified compounds and the in vitro data of
58 derivatives. Of these, 33 compounds were potent deriva­
tives, demonstrating IC50 < 50 nM activities in the hOGA
enzymatic assay. Particularly, the 2,3,4,5-tetrahydro-
1 H-benzo[d]azepine scaffold, connected at N-1 position via
a methylene linker to aromatic groups, were interesting com­
binations. It included 5,6- bicyclic heterocycles, especially
benzo[d]thiazole derivatives, e.g. molecules 217–221
(Figure 41). Other groups with promising enzymatic activity
are partially saturated bicyclic heterocycles, such as 2,3-dihy­
drobenzofuranes or 2,3-dihydrofuro[3,2-b]pyridines, e.g. 223
and 6,6-bicyclic heterocycles, quinaxolines, e.g. 224.
Changing the spatial orientation of the two parts of the mole­
cule resulted in a decrease in activity; compare IC50 < 50 nM
versus IC50 = 200–100 nM, derivatives 221 (2,3,4,5-tetrahydro-
1 H-benzo[d]azepine) and molecule 222 (2,3,4,5-tetrahydro-
1 H-benzo[c]azepine), respectively. Changing the position of
a Cl-atom to the aromatic ring of the tetrahydro-1 H-benzo[d]
azepine scaffold led to a decrease in enzymatic hOGA activity;
the 6-chloro-7-methoxy derivative versus 7-chloro-8-methoxy,
compounds 218 and 219, respectively.
In the third patent [119] from February 2020 were disclosed
226 compounds containing spirocyclic piperidines as the cen­
tral core. The patent application revealed pharmacological
data for 58 compounds, of which seven demonstrated IC50
< 50 nM in the enzymatic hOGA assay. The majority of the
exemplified compounds contained a 1,3,8-triazaspiro[4,5]
decane-2,4 dione core, connected at the N-8 piperidine with
thiazoles, benzothiazoles or dihydrobenzofuranes via
a methylene linker. Many substituents were introduced at
the N-3 position of the imidazolidine-2,4-dione, including
alkyl chains, substituted phenyl and heteroaromatic rings.
Among these, aromatic substituents linked either directly or
via a methylene linker to N-3 were beneficial for potency, e.g.
226 and 227 versus 225, depicted in Figure 42. Additional
substitution at N-1 decreased the potency, as exemplified by
molecule 228. Variations of the central core included spiro
[indoline-3,4ʹ-piperidin]-2-one, diazaspiro[4.5] decane,
 EXPERT OPINION ON THERAPEUTIC PATENTS 23

Figure 42. Representative spirocyclic piperidine OGA inhibitors from Asceneuron S.A.

2,8-diazaspiro[4.5]decan-1-one and 1,3,8-triazaspiro[4.5]decan- 2.4. Janssen Pharmaceuticals

2-one derivatives 229–232, and led to a decrease in potency.
Janssen published 11 patent applications that disclosed three
Asceneuron S.A. published a patent application in
main OGA chemotypes, i.e. saturated cyclic amines, spirocyclic
August 2020, and it described 165 fused tetrahydro-azepine
diamines and azaindoles. Thus, three patent applications from
derivatives as OGA inhibitors[120]. The document disclosed
2018 described various 5- and 6-membered heterocyclic
the pharmacological data for 17 compounds. The tetrahydro-
amine series as OGA inhibitors. The first application discloses
azepine scaffold was fused with structurally diverse saturated
64 examples of 5- and 6-membered cyclic amines substituted
and aromatic 5-membered rings and eleven OGA inhibitors
at N-1 either with a heteroaryl sulfonyl or, in most cases,
with IC50 values below the 50 nM range. Figure 43 shows
benzyl-like radicals; the 2-acetamidothiazole-5-yl radical is
interesting examples. The N-6 position of the tetrahydroaze­
the most frequently used moiety[121]. All examples described
pine ring was connected via a methylene linker to aromatic
in this patent application present a 6,5-heterobicyclic substi­
substituents such as benzothiazole 233, N-(5-methylthiazol-
tuent attached through the 5-membered ring to the C-3 posi­
2-yl)acetamide 234 and dihydrobenzofurane 235. Changing
tion of the central heterocyclic scaffold, in most cases,
the way the heteroaromatic moiety is linked to the 7-mem­
a piperidine or pyrrolidine ring. Figure 44 depicts representa­
bered rind and thus the orientation of this aromatic group
tive examples 237–240. A second publication disclosed
decreased the hOGA potency; compare molecules 234
6.5-heteroaromatic bicyclic systems direct-linked or connected
(2-methyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine) and
via a spacer to the C-3 position of piperidine, morpholine or
235 2-methyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine
piperazine as OGA inhibitors[122]. Out of the 109 examples,
albeit no matched pair.
100 derivatives contain the 2-acetamidothiazole group
24 J. M. BARTOLOMÉ-NEBREDA ET AL.

Figure 43. Representative fused tetrahydro-azepine OGA inhibitors from Asceneuron S.A.

Figure 44. Representative 6,5-heterobicyclic OGA inhibitors from Janssen.


Figure 45. Representative monoheterocyclic OGA inhibitors from Janssen.
attached to the N-1 atom of the central core. The patent
application disclosed enzymatic OGA activity data for all com­
pounds and cell-based assay data for representative examples.
Figure 44 shows representative examples (241–244) from this
application.
Interestingly, sulfonamide examples described containing
a morpholine (243) or piperazine (244) central scaffold dis­
played good inhibitory values in the OGA enzymatic assay
while not showing activity in the cell-based assay at the high­
est concentration tested.
A third application described 171 examples of piperidines
and pyrrolidines substituted at C-3 by a monocyclic hetero­
cycle[123]. The application described substituted N1-linked
heteroaryl sulfonyl or benzyl-like radicals. The groups attached
at the C-3 position of the piperidine or pyrrolidine, via a direct
bond or a methylene spacer, are monocyclic aromatic
heterocycles.
The 2-acetamidothiazole-5-yl and 2,6-dimethylpyridin-4-yl
radicals are the most frequently described heterocycles in
substituents at N-1 and C-3 positions. Compounds 245–248
in Figure 45 are among the most potent examples from this
patent application.
The Janssen scientist reported novel spirocyclic diamines
with OGA inhibitory activity in 2018[124]. This patent applica­
tion disclosed 69 examples where a 2-acetamidothiazole-5-yl
group connected via a methylene linker to a 2,7-diazaspiro
[4,4]nonane, which is the common substructure to 45 mole­
cules. Sixty-seven derivatives have a six-membered monocyc­
lic heteroarene directly linked to the N-2 position of the spiro-
bicyclic central scaffold. They disclosed a set of eleven N-1
alternative bicyclic systems – including benzodioxane, pyrido­
dioxane, quinoline, indazole and benzothiazole – to the acet­
amidothiazole group. Figure 46 displays the inhibitory
EXPERT OPINION ON THERAPEUTIC PATENTS 25
activities in the hOGA in vitro assay and cell-based assay for
a subset of compounds; the most potent derivative is 249.
Additional representatives containing a benzothiazole (250) or
benzodioxane (251) N-1 substituents are also shown in
Figure 46. More recently, Janssen scientists have reported
a more extensive characterization of one of the compounds
disclosed in this patent application, confirming it as a potent
metabolically stable and orally bioavailable OGA inhibitor with
modest central penetration[125].
In 2019 Janssen scientists published nine new patent
applications disclosing novel families of OGA inhibitors. On
December 26th, five applications revealed mostly piperi­
dines and pyrrolidines substituted at position C-3 with
a great variety of aromatic heterocycles and bearing at
N-1 fully and partially saturated heteroaromatic rings con­
nected through a methylene spacer optionally substituted
with a small alkyl group [126–130]. Thus, an application
disclosed 198 examples where the central scaffold is
a piperidine ring. The piperidine ring was substituted at
the C-3 position by a 6-membered heteroaryl substituent
via a linker of variable length (0–2 atoms All examples
from this patent application contain a partially saturated
heterobicyclic ring connected through a methylene linker
to the N-1 position of the central scaffold. Figure 47
depicts compounds (253–256) displaying suitable OGA
inhibitory enzymatic activities in the 1.3–10 nM range.
Moreover, the patent application disclosed ex vivo recep­
tor occupancy data of the compounds 255 and 257. Oral
administration of 25 mg/kg of compound 257 achieved
nearly full occupancy (Occ. 93%) in the forebrain at the
24 h post-dose time point.
Piperidine OGA inhibitors containing 6,6-bicyclic aromatic
heterocycles at N-1 position were published in a patent
26 J. M. BARTOLOMÉ-NEBREDA ET AL.

Figure 46. Representative spirocyclic diamine OGA inhibitors from Janssen.

Figure 47. Representative piperidine OGA inhibitors containing a partially saturated heterobicyclic N-1 substituent from Janssen.

Figure 48. Representative piperidine OGA inhibitors containing an aromatic 6,6-heterobicycle as N-1 substituent from Janssen.
Figure 49. Representative piperidine OGA inhibitors containing an aromatic 6,5-heterobicycle as N-1 substituent from Janssen.
application disclosing ten examples. All compounds described
have a 2,6-dimethyl-4-(piperidin-3-ylmethyl)pyridine as
a common substructure connected to a quinoline, naphthyr­
idine or quinoxaline ring via a methylene spacer. The most
potent examples from this patent application are compounds
257 and 258 (Figure 48) containing a 1,5-naphthyridine and
1,8-naphthyridine ring, respectively.
The Janssen researchers disclosed in 2019 109 OGA inhibi­
tors containing piperidine and pyrrolidine scaffolds. As in pre­
vious patent applications, these piperidine and pyrrolidine
scaffolds were substituted at the C-3 position with
a monocyclic heteroaromatic ring connect via a 0–2 atom
spacer. The methylene spacer connects a 6,5-bicyclic aromatic
heterocycle to the N-1 of the central scaffold in all examples.
Representative compounds showing suitable inhibitory activ­
ities in the OGA enzymatic and cellular assay are compounds
259–262 (Figure 49). Derivative 262 showed negligible occu­
pancy of the OGA enzyme 24 hours post-dose following
25 mg/kg oral administration.
Monocyclic aromatic heterocycles were also reported as
suitable substituents at N-1 in a patent application disclosing
a series of C-3 substituted piperidines and pyrrolidines. In
EXPERT OPINION ON THERAPEUTIC PATENTS 27
general pyrrolidine-containing examples are less potent than
their corresponding piperidine matched-pairs. Pyrazole, pyri­
dine and thiophene, combined with a 2,6-dimethyl-4-(piper­
idin-3-ylmethyl)pyridine, are among the heterocycles leading
to more potent OGA inhibitors in the set of 165 examples
disclosed in this case. Figure 50 depicts representative exam­
ples 263–266.
Janssen scientists also published a patent application dis­
closing 129 pyrrolidines bearing a partially saturated hetero­
bicyclic ring connected through a methylene linker to the N-1
position. In all examples from this case, the methylene linker is
also substituted with a methyl group. In most compounds,
a methylene or oxygen spacer links the C-3 position of the
pyrrolidine to a 6-membered heteroaromatic ring. Examples
displaying good OGA inhibitory activity are compounds 267–
270 in Figure 51.
Piperidines substituted at the C-4 position by
a 6-membered heteroaromatic ring connected via a 1- or
2-atom spacer were published on December 26th in a patent
application describing 169 examples[131]. In most cases, they
comprise substituted pyridine and pyrimidine rings linked
through an oxygen atom to the C-4 position of the piperidine
28 J. M. BARTOLOMÉ-NEBREDA ET AL.

Figure 50. Representative piperidine OGA inhibitors containing an aromatic monocycle as N-1 substituent from Janssen.

Figure 51. Representative pyrrolidine OGA inhibitors containing a partially saturated heterobicyclic N-1 substituent from Janssen.

ring. This application also disclosed fully unsaturated aromatic
6,5-bicycles and partially saturated hetero bicycles connected
via a methylene linker to the N-1 atom of the piperidine core;
in many examples, the methylene linker contained a methyl
group. Figure 52 displays potent OGA inhibitors from this
patent application (271–274). They used an ex-vivo protocol
to assess the forebrain’s occupancy after 24 h post-
administration orally of compounds 271, 273 and 274.
Gratifyingly, compounds 271 and 273 demonstrated full occu­
pancy of the target at 25 mg/kg dose.
Finally, two additional patent applications from Janssen
disclosed substituted pyrrolo[3,2-c]pyridine compounds as
OGA inhibitors on 26 December 2019. In both publications,
the pyrrolo[3,2-c]pyridine core contains an aniline or an
amino-heterocycle at the C-4 position of the central scaffold.
Many of the examples comprise an ortho-ortho disubstitution.
In the first patent application, 110 out of the 114 examples
given have at the N-1 position an N,N’-dimethylacetamide
function[132]. The derivatives show, in general, very high
activities in the OGA enzymatic and cellular assays.

Figure 52. Representative 4-substituted piperidines OGA inhibitors from Janssen.
Compounds 275–278 are the most potent examples disclosed
in this application (Figure 53). The second application revealed
209 compounds[133]. Substituents attached to the N-1 posi­
tion of the pyrrolo[3,2-c]pyridine are, in most cases, lipophilic
alkyl groups optionally substituted with fluorine atoms. Also,
substituted alkyl chains with cyclic ethers, such as oxetane,
were exemplified. Compounds in this patent application are
potent OGA inhibitors in the enzymatic assay, with 94 exam­
ples displaying a pIC50 > 8. Representative compounds 279–
283 from this patent application (Figure 53) are among the
most potent OGA inhibitors described by Janssen to date.
2.5. Eli Lilly and Company
Researchers from Eli Lilly published six patent applications
between 2018–2020. Thus, in August 2018[134], they claimed
N-[4-fluoro-5-[[(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-
3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide 245
(Figure 54), and its diastereomers, as OGA inhibitors. They
measured the activity of molecule 245 in a biochemical
assay that utilized fluorescein di-N-acetyl-β-N-acetyl-D gluco­
saminide as a fluorogenic OGA substrate. It amounted to an
IC50 of 2.36 nM. The whole-cell assay, which utilized TRex-293
cells expressing P301S-1N4R tau protein, revealed an inhibi­
tory OGA activity of 245 of 21.9 nM (Figure 49).
A second patent published in November 2018 [135]
claimed a close analogue of 284. Instead of the 5-methyl-
1,2,4-oxadiazol-3-yl derivative 284, they disclosed a 5-methyl-
1,3,4-oxadiazol-2-yl group (Figure 54, 285), and its diastereo­
mers, as OGA inhibitors. This compound demonstrated OGA
inhibition in the enzymatic and cellular assays, having an IC50
= 2.13 nM and 22.6 nM, respectively.
EXPERT OPINION ON THERAPEUTIC PATENTS 29
In December 2019 a third application published [136] covering
a small set of 4 6-[1-[4-(5-methyl-1,3,4-oxadiazol-2yl)-1-piperidyl]
ethyl]-2,3-dihydrofuro[2,3-b]piridine derivatives. The compounds
only differ in the presence or absence of a fluorine atom at
position 5 of the 2,3-dihydrofuro[2,3-b]pyridine motif, and both
possible individual enantiomers are claimed (Figure 55, 286 and
287). Whilst the presence or absence of the fluorine substitution
has an almost negligible impact on the OGA inhibitory potency,
both (-) enantiomers show significantly increased potency (~
1 nM) vs the corresponding (+) enantiomers.
In February 2020 another Eli-Lilly application [137] claimed
a N-[5-[[(2S,4S)-4-(5-cyanopyrazin-2-yl)oxy-2-methyl-l-piperidyl]
methyl]-4-fluoro-thiazol-2-yl acetamide (Figure 56, 288) and its
diastereomers, as OGA inhibitors. This compound is a close ana­
logue of 284 and 285 (Figure 54) that contain a cyanopyrazine as
left-hand side heteroaryl instead of a 5-methyl-1,2,4-oxadiazole.
The biological data reported molecule 288 as a sub-nanomolar
OGA inhibitor (IC50 = 0.343 nM) in an enzymatic assay.
Eli Lilly scientists claimed six 6-fluoro-2-methylbenzo[d]
thyazol-yl analogues in another patent application in
March 2020 [138]. Instead of central piperidine, common
to all previous Eli Lilly’s application, the reported com­
pounds contain a 2-methylpyrrolidine as the central scaf­
fold. As a left-hand side motif, all the said compounds
possess an acetylpyrrolidine fused to either a pyrimidine
or a pyridine (different isomers) heterobicyclic system con­
nected to the central pyrrolidine through an oxygen linker.
The described compounds show OGA inhibitory activity
below 1 nM in an enzymatic assay with exemplary com­
pound 289 as the most potent molecule.
Finally, in a patent from 2020 (WO 2020/028141) [139],
researchers from Eli Lilly claimed that combination therapy
30 J. M. BARTOLOMÉ-NEBREDA ET AL.
Figure 53. Representative pyrrolo[3,2-c]pyridine OGA inhibitors from Janssen.
Figure 54. Preferred Eli Lilly OGA inhibitors.
of compounds 284 or 285 with an engineered anti-tau
antibody described in the patent might result in the reduc­
tion of tau pathology in-vivo.
2.6. Biogen MA INC
In September 2019, researchers at Biogen filed a patent appli­
cation in which they disclosed 175 OGA inhibitors[140], vary­
ing from sub-nanomolar (<1 nM) to micromolar (>20 µM)
ranges in an enzymatic biochemical assay which utilized
recombinant full-length hOGA enzyme and 4-MUGlcNac sub­
strate. The OGA inhibitors contained di- and tri-substituted
cyclic amines as the common central core, having the 2-acet­
amidothiazole substituent connected via a methylene linker at
the N-atom of the pyrrolidine or piperidine ring. A flexible
methylene function at the C-3 or C-5 position, dependent on
the group’s priority, links various heteroaromatic groups to the
cyclic amines. Figure 57 shows the selected analogues. Several
5- and 6- membered (hetero)aromatics and bicyclic hetero­
cycles result in excellent in vitro hOGA activity, i.e. molecules
290, 291, 297, 298, and 299. Introducing an additional bulky
 EXPERT OPINION ON THERAPEUTIC PATENTS 31

Figure 55. Representative 2,3-dihydrofuro[2,3-b]pyridine OGA inhibitors from Eli Lilly.

Figure 56. Selected OGA inhibitors from Eli Lilly.

Figure 57. Selected examples of OGA inhibitors from Biogen.

32 J. M. BARTOLOMÉ-NEBREDA ET AL.
Figure 58. Selected pyrrolidine OGA inhibitors from Biogen.
substituent at the C-2, as in 292, lead to a decrease in potency,
IC50 = 270 nM, whereas a methyl group (compound 293) had
a 29-fold improve in enzymatic activity. The addition of two
fluorine atoms to the 3- or 4-position of the piperidine ring
significantly impacted the enzymatic activity, viz. molecule
295, IC50 = 12 nM, molecule 294, IC50 = 450 nM, respectively.
The most active compounds from the patent application are
the disubstituted pyrrolidines 298 and 299 (Figure 57).
Biogen described, in a second application, published in
March 2020, 166 new OGA inhibitors[141]. The compounds
encompass highly potent hOGA inhibitors with several exam­
ples showing sub-nanomolar (<1 nM) enzymatic activity and
single-digit nanomolar activity in a cell-based OGA-tau MSD
assay. Additionally, MDR1-MDCK efflux ratio (B-A/A-B) and
metabolic stability in rat liver microsomes (expressed as %
of the rat hepatic blood flow Qh) are reported for a large
subset of examples. In this application, the described OGA
inhibitors contain either a 3-heteroaryloxy-piperidine or pyr­
rolidine as central core connected via a methylene linker to
the same 2-acetamidothiazole motif as in the previous appli­
cation. Figure 58 shows representative molecules and rele­
vant SAR. Thus, of the compounds containing
a 5-methoxypyridine, a substituent highly represented, com­
pound 300 is among the most potent, with low efflux poten­
tial and moderate metabolic stability. A methyl at position 2
of the pyrrolidine and a specific stereochemistry seem crucial
for potent OGA inhibitory activity. The deletion of the
2-methyl or changes in the pyrrolidine stereochemistry
resulted in a significant drop in potency, i.e. compounds
301, 302 and 303. Whilst replacing the pyrrolidine with
 EXPERT OPINION ON THERAPEUTIC PATENTS 33

Figure 59. Selected OGA inhibitors from Biogen.

Figure 60. Selected 4-heteroaryloxy-2-methylpyrrolidine OGA inhibitors from Biogen.

Figure 61. Selected 4-heteroaryloxy-2-methylpyrrolidine OGA inhibitors from Biogen.

piperidine or introducing a fluorine atom on the 2-acetami­
dothiazol had an almost negligible impact on the com­
pounds’ activity, those modifications resulted in
a significant decrease in metabolic stability (304 and 305,
respectively). Additionally, several deuterated analogues of
300 are reported, although this modification had no overall
effect on the molecules’ properties, e.g. molecule 306.
Finally, an analogue of compound 300, a 13C radiolabeled
on the pyrimidine, is described, and this modification also
doesn’t affect the molecule’s properties.
Biogen claimed, in a subsequent application published
in June 2020, similar compounds to the previous ones. The
central piperidine or pyrrolidine was replaced by morpho­
line, piperazine, oxazepane or diazepane[142]. The right-
34 J. M. BARTOLOMÉ-NEBREDA ET AL.
Figure 62. Selected examples of pyrrolidine derivatives as OGA inhibitors from Summit Corporation.
hand side 2-acetamidothiazole motif and the left-hand side
aryl or heteroaryl, both connected to the central core by
small linkers, are maintained. Figure 59 details the most
active compound of this application, compound 308, and
relevant SAR. Thus, the introduction of a second methyl
substituent on the pyridine in 270 decreased potency by
6-fold versus 309. Replacement of the morpholine by
piperazine or methyl piperazine reduced the in vitro activ­
ity 5-fold, e.g. molecules 310 and 311. The additional
deletion of the methyl at the piperazine position
decreased the in vitro potency significantly. Central ring
expansion to either oxazepane or diazepane also reduced
the enzymatic activity, with 314 being the most promising
analogue but still 10-fold less potent than 308. Finally, the
right-hand side spacer lengthening also resulted in
reduced potency (314).
Another application described 174 Bicyclic ethers, pub­
lished in August 2020 [143]. Although Biogen researchers
claim both piperidine and pyrrolidine as a central scaffold,
all the exemplified compounds contain a (2S,4 R)-
4-heteroaryloxy-2-methylpyrrolidine connected again
through a methylene spacer to a 2-acetamidothiazole. In
this case, the document revealed that the left-hand side
comprised many diverse 5,6 and 6,6 bicyclic heteroaryl sys­
tems. The claimed compounds are highly potent OGA inhi­
bitors in an enzymatic biochemical assay, and more than
two-thirds of the described compounds show sub-
nanomolar (< 1 nM) potencies. Figure 60 shows representa­
tive compounds from this application (315–317).
Finally, the last patent application from Biogen published
in September 2020 [144] and describes 43 azetidinyl-
containing OGA inhibitors. In contrast to the previous
cases, using a smaller azetidine instead of piperidine or
pyrrolidine as central core resulted in an overall slightly
less potent OGA inhibition, and the reported potencies
range between 10 and 1500 nM. A 2-acetamidothiazol is
constant as a substituent on the azetidine nitrogen, and
different left-hand side heteroaryls (both monocyclic or
bicyclic) are connected to the 3-position of the azetidine
core through a 1 or 2 atom linker of varying nature.

Figure 61 depicts the most potent compounds 318–320. In
analogy with some of the previous cases, introducing
a methyl substituent at position 2 of the azetidine core
seems to impact potency (i.e. 318 versus 320) positively.
2.7. Summit corporation PLC
In September 2012, scientists at Summit Corporation PLC pub­
lished an application in which they claimed pyrrolidine deriva­
tives as selective OGA inhibitors[145]. They disclosed 128
compounds. They measured the enzymatic hOGA activity, and
the selectivity against h-β-hexosaminidases (hHEXA/B) was
reported for 72 compounds. These compounds demonstrated
inhibition of hOGA with IC50 values ranging from < 3 nM to
224 µM, whereas selectivity vs hHEXA/B varied from 0.02 to >
65,000 fold. Figure 62 reveals some of the preferred examples, i.e.
321–324. They all contain a common (2 R,3S,4 R,5 R)-3,4-dihy­
droxy-5-(hydroxymethyl)pyrrolidin-2-yl)-N-methylacetamide
core. The cellular activities were also reported for a small selec­
tion of compounds. In some cases, a large cell shift was observed,
most likely due to a suboptimal cell permeability, e.g. molecule
322, cell shift > 85x.
3. Conclusion
We reviewed the existing patent literature between March 2008
and March 2021 on OGA inhibitors. Sixty-five patent applications
from different companies comprising large pharma and biotech
have been summarized and relevant chemotypes extracted.
These include both carbohydrate derivatives as well as non-
sugar-based structures. The high number of patent applications
and the companies engaged in this research area confirm that
OGA inhibition is a fascinating and promising novel target in AD
and related neurodegenerative disorders.
4. Expert opinion
Neurodegenerative disorders in general, and AD in parti­
cular, represent an enormous challenge for an increasingly
aging population in terms of a social and economic bur­
den, especially since there are no available treatments that
can significantly impact these diseases’ progression. The
availability of high-quality tool compounds suggested
a role for O-GlcNAcylation in neurodegenerative disorders
such as AD. It could prevent the accumulation of hyper­
phosphorylated tau protein in the brain, which has
prompted enormous interest in searching OGA inhibitors
amenable for human testing to confirm its potential. This
interest has resulted in multiple companies engaged in
research programs that have yielded a diverse set of che­
motypes, both carbohydrate and non-carbohydrate
derived, suggesting that OGA inhibition is suitable for
small molecule intervention. Additionally, this diversity of
chemical matter could be of great help to circumvent
eventual structure-based toxicities that could hamper the
validation of the role of OGA inhibition in humans. These
efforts have culminated in identifying three OGA inhibitor
clinical assets (MK-8719 from Merck/Alectos, ASN-120290
EXPERT OPINION ON THERAPEUTIC PATENTS 35
from Asceneuron S.A. and LY-3,372,689 from Eli Lilly) that
have progressed in Phase I clinical trials so far. Although
OGT and OGA manage the O-GlcNAcylation cycle, and OGA
is a highly ubiquitous enzyme with many client proteins,
all the data confirms a promising benign profile for OGA
inhibition after single and multiple ascending doses in
healthy volunteers. Finally, suitable OGA PET tracers have
already enabled the confirmation for target engagement in
healthy volunteers’ brains. It will undoubtedly be of crucial
support for proper dose selection for future PoC Phase II
studies that, in the end, are essential to shed light on the
great promises held by OGA inhibition for the manage­
ment of AD and other tauopathies.
Funding
This paper was not funded.
Declaration of interest
All authors are employees of Janssen Research and Development. The
authors have no other relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript. This
includes employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or pending, or
royalties.
Reviewer disclosures
A reviewer on this manuscript has disclosed that they are an employee of
Alectos Therapeutics, which is engaged in developing OGA inhibitors as
therapeutics. All other peer reviewers on this manuscript have no relevant
financial or other relationships to disclose.
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