Bioorganic & Medicinal Chemistry Letters 29 (2019) 1968–1973

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Bioorganic & Medicinal Chemistry Letters

journal homepage: www.elsevier.com/locate/bmcl

Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as T

selective calpain inhibitors with enhanced metabolic stability
Katja Jantosa, , Andreas Klinga, , Helmut Macka, Wilfried Hornbergera, Achim Moellera,
⁎ ⁎

Volker Nimmrichb, Yanbin Laoc, Marjoleen Nijsenc

a
AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, Knollstrasse, 67061 Ludwigshafen, Germany
b
AbbVie Deutschland GmbH & Co. KG, DMPK-BA, Knollstrasse, 67061 Ludwigshafen, Germany
c
AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064-6125, United States

ARTICLE INFO ABSTRACT

Keywords: Aberrant activation of calpain has been observed in various pathophysiological disorders including neurode-
Calpain inhibition generative diseases such as Alzheimer’s Disease. Here we describe our efforts on ketoamide-based 1-benzyl-5-
Cysteine protease inhibition oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic
Ketoamide liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-
Alzheimer’s Disease
957, Alicapistat) proceeded to clinical phase I studies.

Calpains are intracellular, proteolytic enzymes from the cysteine
protease family constitutively expressed in the inactive form. They are
involved in several physiological processes like cytoskeletal re-
modeling, modulation of signal transduction pathways, platelet acti-
vation, cell differentiation and apoptotic cell death. Calpain 1 (µ-cal-
pain) and 2 (m-calpain) are ubiquitously expressed and calcium-
dependent with µ-molar or m-molar calcium concentrations required
for their respective activation.1 Calpain activity is tightly controlled by
the natural protein inhibitor calpastatin, which only binds to activated
calpain. Overactivation of calpain has been observed in various pa-
thophysiological disorders, like ischemia of the heart, kidney, lung,
liver or the central nervous system (e.g. stroke), inflammations, in-
fectious diseases, muscular dystrophies, cataracts of the eyes, diabetes,
HIV disorders, injuries to the CNS (e.g. brain trauma), Alzheimer's,
Huntington's, Parkinson's diseases and Multiple Sclerosis.2,3
Activated calpain has been found in plaques and neurofibrillary
tangles of the Alzheimer’s Disease (AD) patients brain, and has been
shown to trigger multiple pathogenic processes of AD such as synaptic
dysfunction, β-amyloid production, tau pathology and neurodegenera-
tion.4–6
Overexpression of calpain has been shown to promote amyloid
plaque formation and neuronal degeneration, whereas inhibition of
calpain via overexpression of the natural inhibitor calpastatin was
shown to restore synaptic function and prevent neurodegeneration in
different transgenic mouse models related to AD.7–9 Therefore, inhibi-
tion of calpain represents an attractive approach for the potential
therapeutic treatment of Alzheimer’s Disease.
Over the last two decades numerous calpain inhibitors have been
described,2,10–12 with the vast majority of these compounds built in a
modular concept containing a peptidic backbone and an electrophilic
warhead (Fig. 1). This warhead, typically a ketoamide or a (masked)
aldehyde, covalently interacts with the active site cysteine of calpain
thus acting as covalent reversible inhibitor. Major limitations of the
calpain inhibitors described so far were either their lack of selectivity
versus other cysteine proteases and poor drug like properties resulting
in unfavorable pharmacokinetics and no or insufficient bioavailability.
Starting from the prototypic calpain inhibitor A-705253 we identified
ketoamide-based 2-(3-phenyl-1H-pyrazol-1-yl)nicotinamides as novel
calpain inhibitors with improved profile.13
In particular A-953227 showed potent inhibition of calpain com-
bined with high selectivity versus related cysteine protease cathepsins,
other proteases and receptors. In addition, the compound demonstrated
broad efficacy in a set of preclinical models relevant to AD. However,
low stability against carbonyl reductases led to significant formation of
the inactive hydroxamide metabolite in human, leading to low bioa-
vailability as well as short effective half-life in a Phase 1 study

Abbreviations: ADME, absorption, distribution, metabolism, excretion; Cal, calpain; Cat, cathepsin; cyno, cynomolgus monkey; cytCl, cytosolic clearance; EDCI, 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide; F, bioavailability; HOBt, hydroxylbenzotriazole; mCl, microsomal clearance; Papp, apparent permeability; PK,
pharmacokinetics
⁎
Corresponding authors.
E-mail addresses: katja.jantos@abbvie.com (K. Jantos), andreas.kling@abbvie.com (A. Kling).

https://doi.org/10.1016/j.bmcl.2019.05.034
Received 2 April 2019; Received in revised form 16 May 2019; Accepted 17 May 2019
Available online 18 May 2019
0960-894X/ © 2019 Elsevier Ltd. All rights reserved.
K. Jantos, et al. Bioorganic & Medicinal Chemistry Letters 29 (2019) 1968–1973

Table 1
Inhibition of calpain 1 and cathepsin selectivity for compounds 3–11.

Fig. 1. General structure of ketoamide-based calpain inhibitors showing the

essential pharmacophores required for activity and selectivity.

conducted.14
Here we describe our efforts on ketoamide-based 1-benzyl-5-ox-
opyrrolidine-2-carboxamides as a novel series of calpain inhibitors
broadening structural diversity beyond the phenyl-1H-pyrazol-1-yl)ni-
cotinamide series as well as mitigating the metabolic liability of car- # P2 Cal 1 Ki [nM] Selectivity ratios Cat/Cal
bonyl reduction.
In two papers Donkor et al. disclosed peptide-based aldehyde in- CatB CatK CatL CatS

hibitors comprising proline mimetics in P2.15,16 According to the SAR 3 – 129 72 14 4 14

reported there, cyclisation of the inhibitor backbone led to significant 4 268 56 2 12 7
enhancement of cathepsin B selectivity (compound 2, Fig. 2), which
raised our interest in these structures. However, as an aldehyde war-
head is not ideal from a drug-like perspective, we prepared the corre- 5 39 23 22 15 103
sponding ketoamide analogue 3 which showed slightly reduced calpain
inhibition, but retained high selectivity vs. cathepsin B. Based on this
6 528 5 17 6 2
result we started to further investigate this series with the objective to
identify novel, drug-like and selective calpain inhibitors structurally
differentiated from A-953227 and analogues described recently. 7 50 23 1 13 3
Our investigation started with modification of the central P2 part
(Table 1). Shifting the sulfonamide group into the 5-membered ring
diminished calpain inhibition about twofold (compound 4). Replace- 8 101 72 4 3 2
ment of sulfonyl by carbonyl giving the corresponding lactame led to
about 6fold enhanced calpain inhibition for the (R)-, but reduced ac-
9 64 14 4 21 56
tivity for the (S)-epimer (compounds 5 and 6; characterized as dia-
steromeric mixtures, see experimental part).
Compound 5 also showed favorable selectivity versus the closely
10 82 15 2 4 13
related cathepsins B, K, L and S. Further P2 modification by either in-
corporating 3-methylpyrrolidinone (7) or 1-methyl-imidazolinone (8)
as well as ring extension (piperidinone 9 and pyridinone 10) showed an
11 46 4 6 21 41
overall less favorable cathepsin selectivity profile. At this stage we also
cross-checked the impact of P1 variation. Whereas additional phenyl
substituents, e.g. 4-methoxy or 4-trifluoromethyl, were well tolerated analogue 12 and 13 displayed significantly diminished calpain inhibi-
without affecting overall selectivity (data not shown), the corresponding tion, whereas the corresponding 4-pyridyl and cyclohexyl derivatives
P1 n-butyl analogue 11 showed retained calpain inhibition, but reduced 14 and 15 showed only a 4-5fold reduced calpain inhibition combined
cathepsin selectivity, which was similar to the SAR observed in the with less favorable cathepsin selectivity. Phenyl substitution in 2- or 3-
nicotinamide series.13 Based on these results we selected compound 5 position was tolerated, however, as illustrated by the set of selected
containing the 5-substituted (R)-oxopyrrolidine in P2 as lead for further examples shown, the SAR for calpain inhibition was quite flat and
optimization. varied for the different cathepsins of interest (16–20). Interestingly,
We then focused our efforts on variation of the P3 moiety and sys- 2,6-di-substitution (20) resulted in the most potent and selective ana-
tematically investigated the SAR. A representative set of the analogues logue in this series.
prepared is shown in Table 2. Surprisingly, phenyl and neopentyl Recently we reported on carbonyl reduction as a species-specific

Fig. 2. Structure and in vitro inhibition profile of 1 (A-953227) and compounds 2 and 3. Inhibition data for 2 were taken from reference 16. Selectivities (sel.) are
reported as ratios cathepsin/calpain.

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K. Jantos, et al. Bioorganic & Medicinal Chemistry Letters 29 (2019) 1968–1973

Table 2 structure and introduced various substituted alkyl, aryl and hetaryl
Inhibition of calpain 1 and cathepsin selectivity for compounds 5 and 12–20. moieties. A set of selected examples is shown in Table 4. Removal of P3
(27) led to significantly reduced calpain inhibition. As observed pre-
viously, benzyl in P3 was the most favorable moiety in this position,
with substituents in 2-position tolerated best. We therefore focused on
further investigating the SAR of different substituents and substitution
patterns. Most favorable results were achieved with chloro, OCF3 and
CF3 substituents in 2-position (28–30), leading to enhanced calpain
potency in a range of 1.5–2.5fold. However, the most potent analogue
in this set, compound 29, did not meet our selectivity criteria for ca-
thepsin L of > 20fold selectivity. Interestingly, the most potent and
selective P3 moiety from the P1’ unsubstituted amides (2-OCH3, 6-
CF3–benzyl as found in example 20, Table 2) in combination with P1’
# P3 Cal 1 Selectivity ratios cyclopropyl led to a significant loss of potency (example 31). As the P3
Ki [nM] Cat/Cal benzylic position was identified as metabolic hot spot in this series, we
tried to mitigate metabolism, either via additional substitution in this
R CatB CatK CatL CatS
position or introduction of heterocyclic residues with lower lipophili-
5 39 23 22 15 103 city. However, all analogues displayed reduced calpain potency. Com-
pounds 32 and 33 are shown as representative examples with calpain
Ki > 500 nM.
12 > 1350 28 6 7 11 Altogether, from the different analogues prepared, N-cyclopropy-
lamide 22 featured the most favorable profile, and we thus decided to
characterize this compound further with respect to functional efficacy
13 1350 23 7 7 7 in AD related models. In a cellular assay using the prevention of NMDA-
induced spectrin degradation in rat hippocampal slice cultures, 22
showed an IC50 value of 385 nM. In addition, in a model of Aβ oli-
14 180 16 13 9 35 gomer- induced reduction of synaptic transmission in the CA1 area in
rat hippocampal slice cultures, application of 22 completely prevented
the decrease of glutamatergic synaptic strength (Fig. 3).17,18
15 200 8 <1 2 5 Scheme 1 outlines the synthesis of compounds 3–20 in a general
schematic way. The appropriate “P3-P2 acids” employed as starting
material were either commercially available or prepared according to
16 2-CF3 59 17 102 65 524 literature. The synthesis of (2R)-N-(4-amino-3,4-dioxo-1-phenylbutan-
17 2-OCF3 57 5 33 41 127
18 3-CF3 26 15 84 11 85
2-yl)-1-benzyl-5-oxopyrrolidine-2-carboxamide 5 and (2R)-1-benzyl-N-
19 3-OCF3 125 7 61 4 76 (4-(cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-ox-
20 2-OCH3, 6-CF3 36 51 120 387 395 opyrrolidine-2-carboxamide 22 is described as example for the pre-
paration of compounds 4–33. Reductive amination of D-glutamic acid
with benzaldehyde and subsequent cyclisation gave (R)-1-benzyl-5-
metabolic liability of ketoamide-based calpain inhibitors, resulting in oxopyrrolidine-2-carboxylic acid 34. Coupling of the acid with 3-
low bioavailability in cynomolgus and human. This pathway is reflected amino-2-hydroxy-4-phenylbutanamide gave hydroxyamide 35, which
by low stability in liver cytosol (cytClint), which can be used as an in was oxidized to ketoamide 5 using Pfitzner-Moffat conditions. Alter-
vitro screening assay to select analogues with enhanced stability versus natively, acid 34 was coupled with ethyl 3-amino-2-hydroxy-4-phe-
carbonyl reduction.14 PK assessment of compound 5 displayed good nylbutanoate to give ester 36. Ester cleavage and coupling with cy-
oral availability in rat (45%), but no bioavailability in cynomolgus clopropylamine yielded hydroxyamide 37, and final oxidation then
monkey. Cytosolic clearance was found to be highly unfavorable with gave ketoamide 22. Detailed experimental procedures for the synthesis
cytClint values of 185 and 270 µL/min/mg for cyno and human, re- of 5 and 22 as key compounds are given in the Supporting Information;
spectively, confirming again that low cytosolic stability reflects low oral procedures for all other analogues have been reported in Ref. 20.
bioavailability in this species. To address this issue we examined the Final compounds 4–9 and 11–22 were prepared as 1:1 mixtures of
possibility for P1’ extension in the oxopyrrolidine series, since this the corresponding diastereomeres. To address the question of P1 con-
concept had already been applied earlier by us to mitigate carbonyl figuration, we prepared the corresponding R,S and R,R diastereomers of
reduction as metabolic liability. 22, employing either ethyl (3S)- or (3R)-3-amino-2-hydroxy-4-phe-
We prepared more than 50 substituted amides covering broad nylbutanoate in the synthesis. Calpain inhibition was clearly assigned
chemical space and including various P1’ alkyl, o-alkyl, aryl and hetaryl to the R,S-isomer (56 nM vs. > 1000 nM for R;R), confirming our pre-
amides. Tertiary amides were not included since the NH of the P1’ vious results that the P1 S-configuration is favored. However, com-
amide is essential for calpain inhibition. A selected set of examples is parable to what we found in the nicotinamide series,13 we observed
shown in Table 3. In comparison to primary amide 5 all analogues with rapid epimerization at P1 due to the electrophilic group adjacent to the
P1’ extension showed significantly enhanced cytosolic stability, but for P1 chiral center (data not shown), and therefore decided to proceed
most analogues calpain inhibition was reduced in parallel. However, with the diastereomeric mixtures.
some P1’ modifications also had a positive impact on cathepsin se- Compounds 3–33 were evaluated for inhibition of calpain and the
lectivity, an effect most pronounced for analogues 24 and 25 with related most relevant cathepsins B, K, L and S as described previously.13
aromatic moieties in P1’. These analogues showed remarkable se- In addition, all compounds were routinely examined for mCl in rat and
lectivity, in particular for cathepsin B and S. However, due to the low human liver microsomes and cytosolic stability screening.
stability in liver microsomes further advancement was discontinued. The in vitro ADME profile of compound 22 was characterized by
Overall, N-cyclopropylamide 22 displayed the best profile balancing moderate permeability (Papp Caco-2: 9.4 × 10−6 cm/s). Bi-directional
potency, selectivity and metabolic stability. To address reduced calpain efflux studies in MDCKII cells demonstrated that 22 is a substrate for P-
inhibition as a result of P1’ extension we re-visited the P3 part of the glycoprotein (efflux ratio: 10.5), but not for breast cancer resistance

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K. Jantos, et al. Bioorganic & Medicinal Chemistry Letters 29 (2019) 1968–1973

Table 3
Inhibition of calpain 1, cathepsin selectivity and in-vitro clearance for compounds 5 and 21–26.

# P1’ Cal 1 Ki [nM] Selectivity ratios Cat/Cal mCl* cytCl*

CatB CatK CatL CatS rat hu hu

5 H 39 23 22 15 > 100 < 23 27 > 70

21 Et 165 55 85 44 60 < 23 < 23 4
22 130 42 74 42 > 100 < 23 28 <1

23 110 66 27 20 130 > 100 37 1

24 70 296 88 37 > 400 > 100 > 70 5

25 48 104 70 34 286 > 100 > 70 3

26 OCH3 4360 – – – – nd nd nd

* Units of µL/min/mg. Ranges for human intrinsic cytosolic clearance and qualifiers assigned: 0–14 stable, 14–70 moderate, > 70 instable.

protein (efflux ratio: 0.9). Protein binding was low in human plasma
with unbound fraction of approximately 0.3. 22 had good liver mi-
crosomal and hepatocyte stability across rat, dog, monkey, and human.
As compared to the P1’ un-substituted ketoamides 22 also displayed a
much improved liver cytosolic stability in human and monkey in-
dicating a significant improvement on metabolic liability of carbonyl
reduction. This was supported by non-detectable level of hydroxyamide
metabolite in both human and monkey hepatocytes. An in vitro meta-
bolism study using [3H]-labeled 22 suggested that metabolism pri-
marily occurred at the N-benzyl oxopyrrolidine moiety via N-de-
benzylation, whereas carbonyl reduction to form hydroxyamide
metabolite was a minor metabolic pathway. CYP phenotyping studies
suggested that CYP3A4 and 3A5 were the primary CYP isoforms for
metabolism.
The pharmacokinetic behavior of 22 was evaluated in CD-1 mice,
Sprague–Dawley rats, beagle dogs, and cynomolgus monkeys (Table 5).
The pharmacokinetic profile was characterized by low to moderate
mean plasma clearance values (CLp) in mouse, rat, and dog (0.13–1.04
L/hr•kg), while high in monkey (1.98 L/hr•kg). Mean steady-state vo-
lume of distribution values (Vss) were moderate in mouse, dog, and
monkey (0.64–1.8 L/kg), but higher in rat (3.4 L/kg). The plasma
elimination half-life (t1/2) was shortest in dog (1.7 h), followed by 2.3 h
in monkey and approximately 6.0 h in mouse and rat. Oral bioavail-
ability (F) values were high in mouse, rat, and dog (> 80%), while
moderate in monkey (14%). In contrast to compound 5 with 0% oral
bioavailability, 22 displayed an improved oral bioavailability in
monkey, consistent with the enhanced liver cytosolic stability to
minimize the carbonyl reduction. Moderate oral bioavailability and
high Clp value in monkey could be attributed to the first pass meta-
bolism by CYP3A enzymes. 22 partitioned into the rat brain with un-
bound brain to plasma AUC ratio of 0.25.
In summary, we established ketoamide-based 1-benzyl-5-ox-
opyrrolidine-2-carboxamides as a novel series of reversible, covalent
and highly selective calpain inhibitiors. Introduction of the ox-
opyrrolidine moiety in P2 led to analogues with high potency and se-
lectivity such as 5, which was used as lead for further optimization.
However, low stability against carbonyl reductases resulted in sig-
nificant cytosolic reduction of the ketoamide to the corresponding hy-
droxyamide and therefore unfavorable cynomolgus PK. Extending P1’
by incorporation of various aliphatic and aromatic moieties was de-
monstrated as a reliable approach to mitigate the metabolic liability of
carbonyl reduction. Unfortunately P1’ extension also led to diminished
calpain inhibition in parallel. Systematic SAR investigations were un-
dertaken revealing compound 22 (A-1212805) with the most favorable
overall profile balancing calpain potency and metabolic stability com-
bined with an excellent selectivity. In preclinical models relevant to AD
22 demonstrated efficacy with respect to prevention of NMDA-induced
neurodegeneration and Aβ-induced synaptic dysfunction. In addition,
oxopyrrolidine 22 demonstrated an excellent safety pharmacology
profile and proceeded to clinical phase I studies as Alicapistat
(ABT-957).19
Notes
A. M. and Y. L. are former AbbVie employees.
Current affiliation: Y. Lao: Eli Lilly and Company; Lilly Corporate
Center, Indianapolis IN 46,285 U.S. V. Nimmrich: AbbVie Deutschland
GmbH & Co. KG, Development Sciences, Knollstrasse, 67,061
Ludwigshafen, Germany.
This study was sponsored by AbbVie. AbbVie contributed to the
study design, research, and interpretation of data, writing, reviewing,
and approving the manuscript. The authors declare the following
competing financial inter-est(s): The authors are current or former
employees of AbbVie (or Abbott Laboratories prior to separation), and
may own company stock.
Acknowledgments
We thank the global AbbVie calpain project team, in particular the
Ludwigshafen synthesis, analytics and ADME teams as well as the Lake
County ADME team for metabolism studies.

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K. Jantos, et al. Bioorganic & Medicinal Chemistry Letters 29 (2019) 1968–1973

Table 4
Inhibition of calpain 1, cathepsin selectivity and in-vitro clearance for compounds 22 and 27–33.

# P3 Cal 1 Ki [nM] Selectivity ratios Cat/Cal cytCl* mCl*

CatB CatK CatL CatS rat hu hu

22 130 42 74 42 > 100 < 23 28 <1

27 H 9700 – – – – < 23 < 23 <1

28 73 18 93 57 > 130 > 100 > 70 <1

29 50 22 > 200 17 > 200 > 100 > 70 <1

30 90 33 109 162 > 100 > 100 > 70 >1

31 240 13 > 40 > 40 > 40 > 100 > 70 nd

32 545 – – – – 58 42 2

33 530 – – – – 39 27 nd

* Units of µL//mg. Ranges for human intrinsic cytosolic clearance and qualifiers assigned: 0–14 stable, 14–70 moderate, > 70 instable.

Fig. 3. Compound 22 at 100 nM concentration prevents Aβ oligomer-induced deficits in synaptic transmission in rat; data points are shown as mean +/- SEM. The
strength of synaptic transmission is illustrated by the input/output relation in hippocampal slice cultures after stimulation of the Schaffer collateral (p = 0.016 when
compared to untreated oligomer group; p = 0.851 when compared to control.

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K. Jantos, et al. Bioorganic & Medicinal Chemistry Letters 29 (2019) 1968–1973

Scheme 1. Synthetic Route to N-substituted (4-Amino-3,4-dioxo-1-phenylbutan-2-yl)-2-((3-phenyl-1H-pyrazol-1-yl)nicotin¬amides 5 and analoguesa. aReagents and

conditions: a) 3-amino-2-hydroxy-4-phenylbutanamide, EDCI, HOBt, triethlyamine, CH2Cl2 or DMF, 0 °C – rt. b) EDCI, dichloroacetic acid, DMSO, rt. c) benzal-
dehyde, 2 N NaOH, then NaBH4, EtOH, rflx. d) ethyl 3-amino-2-hydroxy-4-phenylbutanoate, EDCI, HOBt, triethlyamine, DMF, 0 °C – rt. e) NaOH, MeOH/H2O, rt. f)
cyclopropyamine, EDCI, HOBt, triethlyamine, DMF, 0 °C – rt. g) EDCI, dichloroacetic acid, DMSO, rt.

Table 5
Pharmacokinetics of 22 in preclinical species following a single IV or PO dose.
Species IV PO

dose t1/2° AUC0-inf CLp Vss dose t1/2° Cmax AUC0-inf F

mouse 2 6.0 15.45 0.13 1.0 2 5.0 2.3 14.46 93.5

rat 2 6.6 1.93 1.04 3.4 2 5.1 0.53 1.91 99.6
dog 1 1.7 1.82 0.61 0.6 1 4.8 0.98 1.51 83.1
monkey 1 2.3 0.51 1.98 1.8 3 1.3 0.098 0.22 14.3

Data provided as mean; ° harmonic mean; Units: Dose (mg/kg); t1/2 (hr); Vss (L/kg); AUC0-inf (µg•hr/mL); CLp (L/hr•kg); Cmax (µg/mL); Tmax (hr); F (%); IV:
intravenous; PO: oral.

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