1408 Current Topics in Medicinal Chemistry, 2007, 7, 1408-1422

A Comparison of Physicochemical Property Profiles of Marketed Oral

Drugs and Orally Bioavailable Anti-Cancer Protein Kinase Inhibitors in
Clinical Development
Adrian L. Gilla,*, Marcel Verdonka, Robert G. Boyleb and Richard Taylorc
a b
Astex Therapeutics, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom, Current
address: Sentinel Oncology, 30 Catharine Street, Cambridge, CB1 3AW, United Kingdom, cCurrent address:
UCB Celltech, 208 Bath Road, Slough, Berkshire, SL1 3WE, United Kingdom

Abstract: This manuscript describes a comparison of the physicochemical properties of marketed oral drugs with those of
45 structurally confirmed orally bioavailable anti-cancer protein kinase inhibitors currently in different phases of clinical
development. It is evident from the data presented that these kinase inhibitors are on average larger (over 110Da), more
lipophilic (over 1.5 log units) and more complex (approximately two more rotatable bonds) than those of marketed oral
drugs. In contrast, hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) counts are not significantly different.
Keywords: Protein kinase inhibitor, physicochemical property, marketed oral drug.

INTRODUCTION involved in the formation of the tumour neovasculature

There are currently over 70 reported small molecule
kinase inhibitors at various stages of clinical trials in
oncology (www.clinicaltrials.gov) which emphasises the
potential importance in targeting protein kinases for treating
human malignancies. The majority of these inhibitors are
directed towards the catalytic ATP-binding site [1]. The
human kinome contains some 518 protein kinases that share
a catalytic domain highly conserved in sequence and struc-
ture. Many kinases playing a crucial role in intracellular sig-
nal transduction [2]. In cancer, unregulated cellular prolife-
ration, differentiation and survival frequently results from
deregulation of protein kinases [3]. The advent of kinase-
targeted therapy for the treatment of human cancer offers a
potential that may be more effective and less toxic than non-
specific cytotoxic therapies, improving both patient survival
and quality of life during treatment [4].
The majority of orally bioavailable protein kinase
inhibitors are intended for use as anti-cancer therapies. To
date, there has only been one published analysis of the
chemical space of kinase inhibitors that have been launched
and/or are currently in clinical trials [5]. Table 1 outlines
forty five (45) orally bioavailable small molecule anti-cancer
protein kinase inhibitors where the chemical structure is
known that have either been launched or are currently in
clinical development. We were interested in a comparison of
the physicochemical properties distribution of this small set
compared to historical oral drugs datasets and to see if there
were some statistically significant differences between them
to help generate insight for our small molecule kinase
inhibitor programs.
Many of the small molecule kinase inhibitors outlined in
Table 1 are directed against growth factor receptors such as
epidermal growth factor receptor - EGFR which are
involved in the cellular proliferative process, and pathways
*Address correspondence to this author at the AstraZeneca,
Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG,
United Kingdom; Tel: +44 (0)1625 233298; Fax: +44 (0)1625
516667; E-mail: andrian.gill@astrazeneca.com
including the vascular endothelial growth factor receptor
(VEGFR) and its downstream components [6]. In addition,
cyclin dependent kinases, which act at the level of the cell
cycle and control progression through its various phases,
have also been extensively targeted. The approval of
imatinib mesylate (gleevec) for the treatment of chronic
myeloid leukaemia (CML) and gastrointestinal stromal
tumour (GIST), gefitinib (iressa), erlotinib (tarceva) for the
treatment of non-small cell lung cancer and more recently
dasatinib (Sprycel) for CML resistant to imatinib, Sorafenib
and Sutent for the treatment of renal cell carcinoma (RCC),
illustrate the potential for success of molecularly targeted
therapies in the field of oncology [7,8].
PHYSICOCHEMICAL PROPERTIES AND DRUG-
LIKENESS - BACKGROUND
There have been numerous efforts to predict druglikeness
and quantify favourable physicochemical properties ranges
for oral bioavailability [9-13]. A number of recent publi-
cations in this area essentially reached similar conclusions,
showing that limited distributions of molecular weight,
lipophilicity and hydrogen bonding are found in oral drugs
(Table 2) [11,12]. In studies by Vieth and coworkers, there
were no meaningful correlations between year of launch and
molecular weight, lipophilicity or target class observed,
strongly suggesting that there has been little divergence from
a defined physicochemical properties range to allow suffi-
cient permeability [12]. Wenlock and co-workers demons-
trated how mean molecular weights, lipophilicity, HBA and
rotatable bonds in earlier development phases were higher
than those of marketed drugs [11]. These and other studies
suggest there may be pressures during drug development that
selects smaller and less lipophilic compounds [14]. It has
also been suggested that this could simply be a consequence
of larger and more lipophilic compounds entering develop-
ment [15].
More recently Leeson and Davis have analysed time-
related differences in the physicochemical profiles of oral
drugs in a range of different therapy areas (drugs launched

1568-0266/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd.

A Comparison of Physicochemical Property Profiles Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14 1409

Table 1. There are Currently 45 Orally Bioavailable Small Molecule Anti-Cancer Protein Kinase Inhibitors in Clinical
Trials/Launched. The Table was Constructed on 10th December 2006 Using Data Sourced from Thompson Pharma [31] and
SciFinder. [32] NSCLC (Non-Small Cell Lung Carcinoma); AML (Acute Myeloid Leukemia); SCLC (Small Cell Lung
Carcinoma); CML (Chronic Myeloid Leukemia); GIST (Gastrointestinal Stromal Tumour); RCC (Renal Cell Cancer)

Small
Primary
Molecule Tumour Development
Small Molecule Inhibitor Structure Kinase Company
Inhibitor types/Indication stage
Target
Name(s)

Iressa H
Cl N O
(gefitinib/Z EGFr/HER-1 AstraZeneca NSCLC Launched
D-1839) O N
N

N O

Head & neck cancer Phase III

Urethral, bladder,
ovarian, prostate, breast Phase II
cancer

OSI
H Pharmaceuticals /
Tarceva N Genentech Inc /
(erlotinib/O EGFr/HER-1 NSCLC Launched
O Roche Holding
SI-774) N O AG / Chugai
O Pharmaceutical Co
N O

Pancreatic cancer Phase III

Colon, glioma, breast,

RCC ovarian, head & Phase II
neck cancer
F

H O
Cl N
CI-1033 / Non-hematological
N EGFr/HER-1, Pfizer / University
PD183805 cancers, ovarian, breast, Phase II
N H Erbb2, AKT of Auckland
(canertinib) lung, head & neck
N O N
O

N H
O O
Tykerb S O N
(lapatanib / N EGFr/HER-1, Refractory metastatic
H
HN Cl GSK Phase III
GW2016 / Erbb2 breast cancer, RCC
572016) O
F

Bladder, head & neck,

Phase II
NSCLC, brain cancer
1410 Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14 Gill et al.

(Table 1) Contd….

Small
Primary
Molecule Tumour Development
Small Molecule Inhibitor Structure Kinase Company
Inhibitor types/Indication stage
Target
Name(s)

O
N

CP-724714 NH O Erbb2 Pfizer Various cancers Phase I

O
N N
H
N

NH

O H
N
BMS- O EGFr/HER-1, Bristol Myers
H Various cancers Phase I
599626 N Erbb2, Erbb4 Squibb
N
N N
N
N

O
N

Cl NH H EGFr/HER-1,
HKI-272 N Wyeth Research NSCL, breast cancer Phase II
N Erbb2
N
O
N O

Various cancers Phase I

CF3

EGFr/HER-1, Takeda
TAK165 Various cancers Phase I
N Erbb2 Pharmaceuticals
N O
N N O

Cl

HN
PTK787 /
N Novartis /
ZK222584 VEGFr-2 Colon cancer Phase III
N Schering AG
(vatalanib)

Glioma, solid tumours,

Phase II
NSCLC
A Comparison of Physicochemical Property Profiles Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14 1411

(Table 1) Contd….

Small
Primary
Molecule Tumour Development
Small Molecule Inhibitor Structure Kinase Company
Inhibitor types/Indication stage
Target
Name(s)

AML, ovarian,
myelodysplastic
Phase I
syndrome, prostate
cancer

O VEGFr-2,
SU-11248
N Kit, Flt3, Pfizer (Sugen) RCC, GIST Launched
(sutent) N
H PDGFr
NH NH
O

Breast, neuroendocrine
Phase II
tumours

H
N O
N
HN S
N F VEGFr OSI NSCLC, ovarian cancer,
CP-547632 Phase II
H2N family Pharmaceuticals solid tumours
O
O
F Br

Br

NH
Vandetanib
F O VEGFr-2,
(zactima / N
AstraZeneca Solid tumours, NSCLC Phase III
Ret, EGFr
ZD-6474)
N O
N

Breast, thyroid tumours,

multiple myeloma,
Phase II
brain, head & neck
cancer

N
Pazopanib N N VEGFr1-3, Advanced / metastatic
(GW- GSK Phase III
Kit, PDGFr renal cancer
786034) N
NH2
N N S
H O O

Solid tumours, NSCLC Phase II

1412 Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14 Gill et al.

(Table 1) Contd….

Small
Primary
Molecule Tumour Development
Small Molecule Inhibitor Structure Kinase Company
Inhibitor types/Indication stage
Target
Name(s)

H
S
N

OCF3
O
N OSI
OSI-930 H VEGFr-2, Kit Various cancers Phase I
Pharmaceuticals

NH2 H H
N N
N
VEGFr1-3,
N Abbott AML, myelodisplastic
ABT-869 O Kit, CSF-1, Phase I
F Laboratories syndrome
PDGFr

VEGFr Metastatic pancreatic

Axitinib
family, CSF- Pfizer cancer, RCC, NSCLC, Phase II
(AG013736)
N
1, PDGFr breast, melanoma

S NH

O NH

Various cancers Phase I

H
N NH
VEGFr GIST, metastatic
AMG706 O family, Kit, Amgen thyroid cancer, NSCLC, Phase II
PDGFr breast, colorectal cancer
N NH

Various cancers Phase I

NH
Colorectal cancer,
mesothelioma, liver,
O
Cediranib ovarian, NSCLC,
O F VEGFr1-3 AstraZeneca Phase II
(AZD-2171) N prostate cancer,
melanoma, solid
N O N tumours

Prostate Phase I
A Comparison of Physicochemical Property Profiles Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14 1413

(Table 1) Contd….

Small
Primary
Molecule Tumour Development
Small Molecule Inhibitor Structure Kinase Company
Inhibitor types/Indication stage
Target
Name(s)

H H
N N

O
Cl O VEGFr
KRN633 Kirin Glioma & solid tumours Phase I
O family
N

N O

Cl

H
N

BAY-57- N VEGFr2,
Bayer AG Various cancers Phase I
9352 N
PDGFr
O N
H
O N

O
VEGFr
SU-14813 Pfizer Metastatic breast cancer Phase II
N N family
O HO H NH NH
O

Various Cancers Phase I

HN F

O VEGFr
BMS- Bristol Myers
family, FGFr Various Cancers Phase I
582664 N Squibb
O
family
N
N O
O
NH2

N
NH2
N
CP-868596 PDGFr Pfizer Various Cancers Phase I
N

N O
O
1414 Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14 Gill et al.

(Table 1) Contd….

Small
Primary
Molecule Tumour Development
Small Molecule Inhibitor Structure Kinase Company
Inhibitor types/Indication stage
Target
Name(s)

Gleevec N H H
(glivec / N N N N N c-Abl, Kit,
Novartis AG CML & GIST Launched
imatinib / O N
PDGFr
STI571)

Intestinal cancer &

Phase III
myeloid leukemia

Glioma, lung, prostate,

Phase II
solid tumours

Nilotinib O
H c-Abl, Kit,
(tasigna / N N F Novartis AG ALL, CML, GIST Phase II
N PDGFr
AMN-107) H F
N F

Leukemia Phase I

O
OH

VEGFr
SU-6668 family, Pfizer (Sugen) Solid tumours Phase II
NH PDGFr, FGFr

O
NH

NH
VEGFr
AEE-788 N family, Novartis AG Solid tumours Phase II
PDGFr, FGFr
N N N
H

F NH2 HN N N
VEGFr
CHR-258 N family, Chiron Corp. Various cancers Phase I
PDGFr, FGFr
N O
H
A Comparison of Physicochemical Property Profiles Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14 1415

(Table 1) Contd….

Small
Primary
Molecule Tumour Development
Small Molecule Inhibitor Structure Kinase Company
Inhibitor types/Indication stage
Target
Name(s)

H
N
O

O Pancreastic cancer,
VEGFr Cephalon / Sanofi-
CEP-7055 prostate cancer & solid Phase I
N family, Tek Synthelabo
tumours

O
N
O
H
O N

Colon, breast, CLL,

Midostaurin N N PKC family, AML, GIST, solid
O Novartis AG Phase II
(PKC-412) H Flt3 tumours & non-
Hodgkin’s lymphoma
O
N

Breast & colorectal

Phase I
cancer
H
O N O

Enzastaurin N N PKC
, Glioblastoma, B-cell

(LY- Eli Lilly Phase III
GSK3
, AKT lymphoma
317615)

N
N

NSCLC Phase II

Multiple Myeloma &

Phase I
solid tumours

Cl O
O
Sorafenib Raf, Ret,
(nexavar / F N VEGFr2, Bayer AG / Onyx
N N RCC Launched
BAY 43- H H VEGFr3, Pharmaceuticals
F F
9006) O N PDGFr, Flt3
H

Hepatocellular
carcinoma, NSCLC, Phase III
melanoma
1416 Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14 Gill et al.

(Table 1) Contd….

Small
Primary
Molecule Tumour Development
Small Molecule Inhibitor Structure Kinase Company
Inhibitor types/Indication stage
Target
Name(s)

Myelodyspalstic
syndrome, AML, head
& neck cancer, breast, Phase II
colon, ovarian,
pancreatic cancer

H
N O
HO O H F

PD- OH N NSCLC, melanoma,

MEK Pfizer Phase II
0325901 breast, colon cancer
F I
F

Solid tumours Phase I

Various cancers,
AEW-541 IGF Novartis AG Phase I
O multiple myeloma
N

N NH2

CYC202 Breast, NSCLC,

Cyclacel
(seliciclib / HN lymphoid leukemia,
CDK family Pharmaceuticals Phase II
R- N glomerulonephritis &
N Inc.
roscovitine) multiple myeloma
HO
N N N
H

SNS-032 O NH
H CDK2, 7, 9, Sunesis / Bristol Solid and hematological
(BMS- S Phase I
S N Aurora A Myers Squibb cancers
387032) N
N O

H Onyx
N N N O
PD-332991 CDK4 Pharmaceuticals / Various cancers Phase I
N Pfizer
N
HN O
A Comparison of Physicochemical Property Profiles Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14 1417

(Table 1) Contd….

Small
Primary
Molecule Tumour Development
Small Molecule Inhibitor Structure Kinase Company
Inhibitor types/Indication stage
Target
Name(s)

O F
O O Hoffmann La
Ro 31-7453 S CDK1, 2, 4 Various solid tumours Phase I
Roche
O N N

H2N N N
H

H
N
O

Lestaurtinib Cephalon / Kyowa

Flt3, TrkA Myeloid leukemia Phase III
(CEP-701) N N Hakko Kogyo
O
H

HO
OH

AML, prostate,
pancreatic cancer, solid Phase II
tumours

H
N O

N
O
AML, glioma,
Tandutinib N Millenium
Flt3 myelodisplastic Phase II
(MLN-518) O Pharmaceuticals
N
syndrome

N O N

Various cancers Phase I

HN

Colorectal cancer,
Aurora A, B,
VX-680 S Vertex / Merck hematological Phase II
Lck
malignancies
N N
N
N N N
H H
N

Various solid tumours,

Phase I
hematological cancers
1418 Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14 Gill et al.

(Table 1) Contd….

Small
Primary
Molecule Tumour Development
Small Molecule Inhibitor Structure Kinase Company
Inhibitor types/Indication stage
Target
Name(s)

OH

HN

N N
MLN8054 Aurora A Millennium Solid tumours Phase I

Cl
F N

Cl
HN O

Dasatinib
S
(sprycel / c-Abl, Fyn, Bristol Myers
N N CML, AML Launched
BMS- N Src, Lck Squibb
354825) HN

OH

Solid tumours, multiple

Phase II
myeloma

Cl
O

AZD-0530 NH Hematological
O O
(AZM- c-Abl, Src AstraZeneca malignancies, solid Phase I
O
475271) N N tumours

N
N O

Cl Cl

O NH
Bosutinib N O CML, leukemia &
c-Abl, Src Wyeth Research Phase I
(SKI-606) various cancers
N O N
N
A Comparison of Physicochemical Property Profiles Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14 1419

Table 2. The Mean Data from Literature Publications on Historical Marketed Oral Drug Datasets, an in House Constructed Oral
Marketed Drugs Dataset and the Orally Bioavailable Anti-Cancer Protein Kinase Inhibitors Dataset

In-house oral
Wenlock Vieth oral Leeson oral data Veber oral Orally bioavailable anti-cancer
Descriptor marketed drugs
oral data[11] data[12] (1983-2002)[13] data[10] protein kinase inhibitors data
data

MW 337 343.7 377 479.8 337.86 457

ClogP 2.5 2.3 2.5 4.27 2.41 4.1

ClogD(7.4) 1.0 ND ND ND 0.93 2.9

HBD 2.1 1.8 1.77 2.29 2.17 2.9

HBA 4.9 5.5 3.74 6.9 3.75 4.4

No. of rotatable
5.9 5.4 6.42 8.39 4.76 6.4
bonds

Wenlock Dataset - Utilised the web-based database “R&D insight” to construct a dataset based on oral compounds in development in the USA up to January 2000 alongside the USA
pharmacopeia “The Physicians Desk reference 1999”. Also used the ACD LogP version 4 and LogD7.4, version 4 to calculate logP and D respectively. The number of hydrogen
bond donors, acceptors and rotatable bonds were calculated using Cerius2 version 4.6. Vieth Dataset - Utilised the 22nd edition of the FDA’s orange book, 2002 editions of MDDR
and CMC3D and Micromedex database to construct a comprehensive database of historical oral drugs. In addition, used the Daylight Chemical Information Systems ClogP
calculation software. Leeson Dataset - Used the Vieth dataset and calculated physical properties using the software that Wenlock employed. [10] Veber Dataset - An in house database
of 1100 compounds was constructed based on Rat oral bioavailability data. In addition, used the Biocyte ClogP 4.0 estimator software as implemented in the Daylight Chemical
Information System Software, V. 4.71. [9] In-house Dataset - An in-house marketed oral drugs dataset was created by minor modification to the Vieth dataset, whereby drug
duplicates and multiple salt forms of the same drug were removed so only the parent drug properties were used for calculation purposes. In addition used the Biocyte ClogP 4.0
estimator software as implemented in the Daylight Chemical Information System Software, V. 4.71 alongside Chemaxon logD.

prior to 1983 and those launched between 1983 and 2002)
[13]. Comparison between these two drug sets identified that
mean values of lipophilicity, percent polar surface area and
HBD count were not significantly different between these
two groups and it is these properties that greatest attention
should be paid for candidate drug selection and particularly
HBD count. In contrast, mean values of molecular weight,
numbers of oxygen and nitrogen atoms, HBA and rotatable
bonds have increased in 1983-2002 oral drugs (by 13-29%).
The results are strongly suggestive that the balance between
polar and nonpolar drug properties is an important,
unchanging feature of oral drug molecules [16].
COMPUTATIONAL METHODS
We assessed the statistically significant differences
between the mean properties of the orally bioavailable anti-
cancer protein kinase inhibitors outlined in Table 1 and those
in an in house constructed set of marketed oral drugs. This
was done by means of a simple bootstrapping simulation,
which repeatedly (1 million times) picked 45 compounds at
random from the in-house oral drugs set [17]. Each time the
mean properties for the selected 45 compounds were
calculated and statistics were collected for each property. For
each property, the probability of obtaining a mean value
greater than or equal to that of the orally bioavailable anti-
cancer protein kinase inhibitors (as in this case all mean
values are larger for the orally bioavailable anti-cancer
protein kinase inhibitor set) is listed in Table 3. For example,
a probabilty of 0.01 means that there is a 1% chance of
obtaining a mean value greater than or equal to that of the
orally bioavailable anti-cancer protein kinase inhibitors by
randomly selecting 45 compounds from the in-house
marketed oral drugs set.
RESULTS AND OBSERVATIONS
One of the clearest findings from this study is that the
mean molecular weight , calculated log P (ClogP), calculated
log D (ClogD) and number of rotatable bonds of the orally
bioavailable anti-cancer protein kinase inhibitors currently in
clinical development are statistically significantly higher
than those of marketed oral drugs (Table 3). The values for
molecular weight and ClogP are at the upper limits of
Lipinski’s cut-off’s that are reflected in the physicochemical
property profiles of his oral drug data set [9]. In contrast,
there is only a marginal increase in HBD count, whilst HBA
count is slightly reduced. A number of potential reasons for
these observed differences can be envisaged.
Initial kinase inhibitor leads can often be very lipophilic
so as to be relatively potent (< 10uM) in a high-throughput
screening assay, making it necessary to be mindful of the
need to ensure a balance of polar and non-polar properties in
lead optimisation to achieve good oral bioavailability. In all
the cases outlined in Table 4, regardless of the starting lead,
the final candidate molecules have increased in complexity
and molecular weight [19-22]. Recognition of this issue in
recent years has lead the drug discovery industry to begin
screening smaller, lower molecular weight or “lead-like”
compounds [23-25]. The templates selected for lead optimi-
sation play a pivotal role in determining the physical pro-
perties of the eventual candidate drug molecule and by
starting from smaller, more ligand efficient templates could
facilitate this process [26,27].
Many kinase lead templates are often unselective for their
target. Exploitation of the ATP-binding site will invariably
add molecular weight and lipophilicity to the lead in order to
increase intrinsic target potency and generate the appropriate
1420 Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14 Gill et al.

Table 3. Bootstrapping Data[17] – The Probability Column Demonstrates the Probability of Picking 45 Compounds Randomly from
the in House Oral Marketed Drugs Set with an Average Property Greater or Equal to that of the Orally Bioavailable Anti-
Cancer Protein Kinase Inhibitor Data Set (Repeated 1 Million Times). Statistical Significant Differences Can be Seen for
MWt, ClogP, ClogD & Number of Rotatable Bonds

Orally bioavailable anti-cancer protein kinase In-house oral marketed

Physicochemical Property Probability (%)
inhibitor dataset drugs dataset

MW 457 337.9 < 0.000001 (< 0.0001%)

ClogP 4.1 2.4 0.000019 (0.0019%)

ClogD(7.4) 2.9 0.9 0.000001 (0.0001%)

HBD 2.9 2.2 0.026 (2.6%)

HBA 4.4 3.8 0.059 (5.9%)

No. of rotatable bonds 6.4 4.8 0.0022 (0.22%)

level of kinase selectivity, Fig. (1). The highly competitive
patent landscape for protein kinase inhibitors may also have
contributed in some cases to enlarged candidate molecules.
An example of this can be seen in Table 4 with BAY 57-
9352, which was developed using PTK-787 as a starting lead
[20].
Fig. (1). The protein kinase ATP binding site. The hydrophobic
back pocket accessibility is governed by the “gatekeeper” residue.
The surface exposed hydrophobic front pocket is able to
accommodate lipophilic moieties on inhibitors which may contain
terminal polar groups to modulate potency and physicochemical
properties. More polar regions such as the ribose and phosphate
binding pockets are outlined in yellow and magenta respectively.
Kinase inhibitors need to be cell permeable as their
targets are intracellular. This positive permeability bias
inherent in the compounds may also offer an advantage in
gut wall permeability leading to improved oral bio-
availability despite significant increases in average MW and
ClogP [16]. In addition, often to afford good cell activity, a
solubilising group is appended to the kinase inhibitor
scaffold (Table 4).
There are many factors that are well recognised as
potentially limiting oral bioavailability [28-30]. More often,
P-glycoproteins (PgP’s) and CYP450’s primarily limit oral
absorption [16] and are significant issues facing the often
planar, lipophilic scaffolds that make up the majority of the
orally bioavailable anti-cancer protein kinase inhibitors in
clinical development. Increasing molecular complexity, infl-
uencing molecular conformation and addition of appropriate
metabolic blocking groups can overcome these issues, but
often at the expense of increased molecular weight, lipo-
philicity and molecular complexity.
A major caveat to retrospective analyses of historical oral
drugs is that they are reflective of drug discovery activities a
decade or more old and so do not necessarily provide a clear
guide to future trends. They provide information about the
properties of the often structurally more simple drugs of the
past aimed at more tractable biological targets, that are not
representative of the greater complexity of modern drugs
required to interact with more challenging biological targets,
such as intracellular protein kinase inhibition or modulation
of protein-protein interactions. Many approaches to address
“drugability” have been emphasised in the discovery phase
over the past decade, including optimisation of ADME
properties, physical form and safety properties in parallel
with the desired biological effects. However, historical
analyses of oral drug properties do encode crucial infor-
mation, not only with respect to solubility and permeability,
but to favourable drug metabolism and pharmacokinetic
properties.
It is also interesting to note that there is little difference
in physicochemical properties distribution between Phase I
A Comparison of Physicochemical Property Profiles Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14 1421

Table 4. Physicochemical Properties Comparison of Selected Examples of Oral Anti-Cancer Protein Kinase Inhibitors and their
Initial Lead Structures

Drug/Clinically
Advanced MW / Initial Lead MW /
Initial Lead Structure Candidate Structure
Protein Kinase ClogP Caveats ClogP
Inhibitor

Low enzyme &

H cell activity,
Gleevec N N N
171.2 / H H poor ADME & 493.7 /
(Imatinib) N N N N N
N 2.5 solubility, 4.5
STI-571 O N
kinase
[19] selectivity

O N Poor ADME
(rapidly
Iressa NH N metabolized in
295.4 / N O 447 /
(Gefitinib) O vivo), low
N 4.8 O HN Cl 5.6
ZD1839 solubility,
N O kinase
F selectivity
[22]

O
O Cl O
O Low enzyme &
Sorafenib (BAY O 332.5 / F N cell activity, 464.9 /
S N N
43-9006) 3.9 H H low solubility, 5.5
N N F F poor ADME
H H O N
H
[21]

Cl
Cl
HN
HN IP position,
N
346.9 / N
poor ADME 409.9 /
BAY 57-9352 N 4.7 (CYP450 4.2
O N
N liabilities)
H
O N
N O
[20]

Table 5. Average Physicochemical Property Values for the Orally Bioavailable Anti-Cancer Protein Kinase Inhibitor Dataset (45
Compounds) Distributed Between Phase I & Launched Drugs (SEM = Standard Error of the Mean)

Descriptor Phase I Phase II Phase III Launched

No. Compounds in each phase 18 15 6 6

Mean MW (SEM) 454 (12) 461 (21) 466 (32) 448 (18)

Mean ClogP (SEM) 4.1 (0.3) 4.0 (0.4) 4.6 (0.5) 4.1 (0.6)

Mean ClogD (7.4) (SEM) 2.7 (0.4) 2.7 (0.5) 3.7 (0.5) 2.9 (0.6)

Mean HBD (SEM) 2.9 (0.3) 3.0 (0.3) 2.3 (0.3) 3.0 (0.5)

Mean HBA (SEM) 4.7 (0.4) 4.1 (0.3) 4.2 (0.5) 4.5 (0.6)

Mean No. of rotatable bonds (SEM) 6.4 (0.6) 6.6 (0.7) 5.3 (1.3) 6.8 (0.7)
1422 Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 14
to launched drug for the orally bioavailable anti-cancer
protein kinase inhibitors (Table 5). This looks markedly
different to the Wenlock data where a steady decrease of
molecular weight was seen moving from Phase I to launched
drug [11]. Care must be taken in over interpretation of this
trend since the orally bioavailable anti-cancer protein kinase
set is statistically small and limited attrition has been
observed to date in this target class. Indeed, to date only six
of the compounds outlined in Table 1 are now marketed
drugs.
CONCLUSION
The properties showing the clearest divergence between
marketed oral drugs and orally bioavailable anti-cancer pro-
tein kinase inhibitors in clinical development are molecular
weight and lipophilicity. Whilst still within the Lipinski
rules, the orally bioavailable anti-cancer protein kinase inhi-
bitors are on average larger (over 110Da), more lipophilic
(over 1.5 log units) and more complex (approximately two
more rotatable bonds) than those of marketed oral drugs
(Table 3). In contrast, hydrogen bond donor (HBD) and
hydrogen bond acceptor (HBA) counts are not significantly
different.
ACKNOWLEDGEMENTS
The authors would like to thank Chris Murray, Miles
Congreve and David Rees for discussions and proof reading
this manuscript.
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Received: December 15, 2006 Accepted: December 15, 2006