Discovery of a potent and selective c-Kit inhibitor for the treatment of inflammatory diseases

Article abstract of DOI:10.1016/j.bmcl.2008.05.089

A potent and selective c-Kit inhibitor 20 was identified through a structure-activity relationship study. In an in vivo mouse model of mast cell activation, 20 blocked the SCF-induced histamine release with an EC₅₀ of 26 nM.

Full text of DOI:10.1016/j.bmcl.2008.05.089

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4137–4141
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a potent and selective c-Kit inhibitor for the treatment
of inflammatory diseases
a
a
a
a,
Ning Chen a, , Roland W. Bürli , Susana Neira , Randall Hungate , Dawei Zhang , Violeta Yu b,
Yen Nguyen b, Yanyan Tudor b, Matthew Plant c, Shaun Flynn b, Kristin L. Meagher d, Matthew R. Lee d,
Xuxia Zhang c, Andrea Itano c, Michael Schrag e, Yang Xu e, Gordon Y. Ng c, Essa Hu a
*
a Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
b Department of HTS and Molecular Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320 and One Kendall Square, Building 1000, Cambridge, MA 02139, USA
c Department of Inflammation, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
d Department of Molecular Structure, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
e Department of Pharmacokinetic and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A potent and selective c-Kit inhibitor 20 was identified through a structure–activity relationship study. In
an in vivo mouse model of mast cell activation, 20 blocked the SCF-induced histamine release with an
EC50 of 26 nM.
Received 4 April 2008
Revised 21 May 2008
Accepted 21 May 2008
Available online 28 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
c-Kit
SCF
Mast cell
Inflammatory diseases
The KIT gene encodes for a tyrosine kinase transmembrane pro-
tein (c-Kit), which functions as the receptor for stem cell factor
(SCF).1,2 C-Kit was first found to be expressed on the surface of
mast cells in 1989.3 Later it was shown to play a critical role in
modulating histamine release from mast cells.4,5 Binding of SCF
to the c-Kit receptor mediates various functions of the mast cell.
It has been demonstrated that SCF induces mast cells survival in vi-
tro, adhesion to extracellular matrix and degranulation, leading to
expression and release of histamine.6 Inhibition of c-Kit may have
therapeutic utility in mast cell associated inflammatory and auto-
immune diseases.7 In a recent study using a murine asthma model,
either down regulation of SCF expression or inhibition of c-Kit
resulted in reduced inflammatory response.8,9 Therefore, blocking
c-Kit signaling may present a potential therapeutic approach for
treating human inflammatory diseases related to mast cells.
Gleevec is a commercially available multi-kinase inhibitor
(c-Kit, bcr-abl, and PDGFR) that has been approved for the treatment
of chronic myeloid leukemia10 and GISTs.11,12 Preclinical studies
have shown that Gleevec also inhibits mast cells and is efficacious
in rodent arthritis models.13,14 Our goal was to identify a more
potent and selective c-Kit inhibitor compared to Gleevec for the
treatment of chronic inflammatory illnesses. Herein, we report
our efforts towards identifying a molecule that fulfills these criteria.
From the screening of our kinase-preferred collection, we iden-
tified compound 1 as a potent small-molecule c-Kit inhibitor. Fur-
ther profiling of this molecule through the MAP kinase and
tyrosine kinase panels revealed a superb selectivity against KDR
(Table 1, 460-fold), yet moderate to poor selectivity against other
kinases, such as p38a, Lck, and Abl. Compared to Gleevec, 1
showed better Lck and Abl selectivity, but the p38
a activity needed
to be attenuated.
P38
to play a crucial role in regulating the biosynthesis of proinflam-
matory cytokines including tumor necrosis factor (TNF ) and
interleukin-1 (IL-1b).15 Inhibition of p38
is a proven therapeutic
a mitogen-activated protein kinase (MAPK) has been shown
a
a
strategy in suppressing inflammation, which we intend to avoid
in our c-Kit inhibitor program for treating similar diseases.
Examination of the structure of 1 reveals some potential liabil-
ities, one of those being the orientation of the two amide groups,
which might lead to amide hydrolysis. Indeed, both amide groups
of 1 were hydrolyzed extensively in vivo (rat), resulting in the re-
lease of aniline-type metabolites.16 To avoid these metabolites, the
amide orientations were reversed to yield 2 and 3. The inhibitory
* Corresponding author. Tel.: +1 805 447 7740; fax: +1 805 480 1337.
E-mail address: chenc@amgen.com (N. Chen).
Present address: ChemDepo, Inc., 4081 Calle Tesoro, Unit G, Camarillo, CA 93012,
USA.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.05.089

4138
N. Chen et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4137–4141
Table 1
Compound 1 vs. Gleevec as potent c-Kit inhibitor
N
N
N
N
O
NH
HN
N
NH
O
NH
O
N
CF3
1
Gleevec
N
c-Kita IC50
(l
M)
p38aa IC50
0.20 (14ꢁ)
(
l
M) (foldb)
KDRa IC50
(l
M) (foldb)
Lcka IC50
(l
M) (foldb)
Abla IC50 M) (foldb)
(l
1
0.014
0.052
>8.33 (>460ꢁ)
>25 (>481ꢁ)
0.24 (17ꢁ)
0.32 (5ꢁ)
0.24 (17ꢁ)
0.11 (2ꢁ)
Gleevec
13.7 (244ꢁ)
a
IC50 values are means of two or more separate determinations.
Fold difference was calculated between enzyme assays.
b
Table 2
Reversed amides of 1 and their kinase activities
N
N
N
N
O
HN
NH
O
O
O
HN
HN
2
3
CF3
CF3
M) (foldc)
c-Kita,b IC50
(
lM)
UT-7 prolifa IC50
(l
M)
p38aa IC50
(l
M) (foldc)
KDRa IC50
(l
Lcka IC50
(l
M) (foldc)
Srca IC50 M) (foldc)
(l
1
2
3
0.014
0.037
0.108
0.012
0.030
0.031
0.20 (14ꢁ)
1.75 (47ꢁ)
0.455 (4ꢁ)
>8.33 (>595ꢁ)
3.53 (95ꢁ)
0.43 (31ꢁ)
0.546 (15ꢁ)
2.76 (26ꢁ)
0.24 (17ꢁ)
1.21 (33ꢁ)
3.76 (35ꢁ)
>5.0 (>46ꢁ)
a
b
c
IC50 values are means of two or more separate determinations.
The ATP concentration in this experiment is 50 M.
Fold difference was calculated between enzyme assays.
l
activities in a variety of enzymatic assays as well as the c-Kit-dri-
ven, cell-based assay17 are shown in Table 2. For the lower-re-
show significant oral bioavailability (ꢀ1% vs. 73% of 1) in rats. Dri-
ven by these unfavorable properties, we next focused on improving
the PK attributes of amide 2 in addition to optimizing the potency
and selectivity.
versed amide 2, the selectivity against p38a improved (47-fold,
vs. 14-fold), even though the enzyme and cell-based potency for
c-Kit decreased by about 3-fold. The doubly-reversed amide 3
was a weaker and less selective c-Kit inhibitor. In rat hepatocytes,
the lower amide of 2 did not appear to hydrolyze as readily com-
pared to 1. Amide 2 was selected for additional studies due to its
We hypothesized that the 5-pyrimidyl unit of compound 2
might contribute to the metabolic liability of the molecule. There-
fore, we set out to identify more stable replacements for this ele-
ment. This region of the inhibitor interacts with the hinge region
of the c-Kit protein; thus, it is expected that new groups containing
an H-bond acceptor would have the highest probability of retain-
ing potency.18 Therefore, a series of heterocyclic amines were
installed following the synthetic sequence shown in Scheme 1.
Coupling of 3-iodo-4-methyl benzoic acid (4) with 3-(trifluoro-
methyl)aniline under standard EDC coupling conditions gave
greater selectivity against p38a and improved metabolic profile.
The metabolic stability and pharmacokinetic profile of amide 2
were examined next. The results of this study are shown in Table 3.
The microsomal stability and pharmacokinetic profile following
intravenous (iv) administration of compound 2 were similar to
those of 1; however, when dosed orally, the compound did not
Table 3
Metabolic stability and pharmacokinetic parameters in male Sprague–Dawley ratsa for compounds 1, 2 and analogs
Metabolic stabilityb
ivc
pod
RLM (
l
l/min/mg)
HLM (
l
l/min/mg)
Cl (mL/h/kg)
Vss (mL/kg)
t1/2 (h)
AUC (ng*h/mL)
Cmax (ng/mL)
F (%)
1
2
9
11
20
<50
48
<50
<100
30
<50
38
<100
<100
<14
1624
1680
854
922
4083
1385
1543
1350
1382
5364
1.4
1.1
3.9
3.3
4.4
2286
75
6153
n/d
861
8
956
n/d
518
73
1
53
n/d
78
1922
a
n = 3 animals per study.
b
c
In vitro intrinsic clearance after incubation with rat/human liver microsomes. Compound concentration = 1
Dosed at 2 mg/kg as a solution in DMSO.
Dosed at 10 mg/kg as a solution in 2% HPMC/1% Tween 80.
lM, microsomal protein = 0.25 mg/mL.
d

N. Chen et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4137–4141
4139
in the pyrimidine pair (for 8, 41-fold vs. for 2, 95-fold). We specu-
lated that the additional NH may allow for a bidentate H-bond
interaction to the linker binding region, which improved affinity
to all kinases, with the exception of KDR. Encouraged by this result,
we then examined the acetylated amino pyrimidine 10 and pyri-
dine 11. For 10, although we observed a ꢀ10-fold decrease in c-
I
O
I
a
b
HN
CF3
O
OH
4
5
Kit potency compared to 8, selectivity against p38
a improved,
however, KDR selectivity diminished. For pyridine 11, the c-Kit po-
tency was maintained or slightly improved compared to 9, selec-
H
N
O
O
c, d
R
MeOOC
O
HN
CF3
HN
CF3
tivity against p38a improved, whereas selectivity against KDR
dropped slightly. We concluded that the overall profiles of com-
pounds 9 and 11 were improved with respect to c-Kit potency
and off-target activity and therefore selected them for detailed
PK studies.
6
Scheme 1. Reagents and conditions: (a) 3-(trifluoromethyl)aniline, EDC, DCM, D-
MF, 78%; (b) Pd(OAc)2, 1,3-bis(diphenylphospino)propane, Et3N, MeOH, CO, 90 °C,
93%; (c) LiOH, THF; (d) RNH2, HATU, Et3N, DMF.
Table 3 shows a comparison of in vitro and in vivo rat PK pro-
files for compounds 2, 9, and 11. When dosed intravenously, ami-
nopyridine 9 exhibited lower clearance (0.85 L/h/kg) and an
elongated half life (3.9 h) compared to 2. Following oral adminis-
tration, 9 showed an oral bioavailability of 53%. The acetylated
aminopyridine 11 gave an iv PK profile similar to that of 9.
Encouraged by the PK properties of 9, we decided to use the
aminopyridine head group as a starting point for further SAR stud-
ies aimed at improving the selectivity profile by modifying the
right-hand side of 9.
To prepare these analogs, we utilized the modified synthetic se-
quence shown in Scheme 2. Hydroxycarbonylation was carried out
on methyl 3-bromo-4-methylbenzoate (12) with Pd(OAc)2 and tri-
phenylphospine in DMF and water under an atmosphere of CO to
give the corresponding benzoic acid 13 in 22% yield. Coupling of
acid 13 with 2,5-diaminopyridine under standard EDC coupling
conditions, followed by hydrolysis of the methyl ester using
amide 5 in 78% yield. Carbonylation was carried out with Pd(OAc)2
and DPPP in methanol under an atmosphere of CO to give 93% yield
of the methyl ester 6. After ester hydrolysis, the liberated acid was
coupled to selected amines using standard conditions to give the
final products.
The biological activity of a select set of analogs bearing hetero-
aromatic head groups are shown in Table 4. By changing the
pyrimidine (2) to pyridine (7), we observed ꢀ2-fold increase in
c-Kit potency; however, selectivity for p38
a and KDR decreased.
With the 5-amino group added to the pyrimidine (8) and pyridine
(9), the c-Kit enzymatic activity improved by 7- and 3-fold, respec-
tively, while p38a selectivity remained poor for both compounds.
Notably, we observed improved KDR selectivity in the pyridine pair
(for 9, 67-fold vs. for 7, 16-fold), and a slight decrease of selectivity
Table 4
Structure–activity relationship: left-hand modification of 2
R
O
HN
O
HN
CF3
R
c-Kita,b IC50
0.037
(
lM)
UT-7 prolifa IC50
0.030
(
lM)
p38aa IC50
1.75 (47ꢁ)
(l
M) (foldc)
KDRa IC50 M) (foldc)
(l
N
2
7
3.53 (95ꢁ)
N
0.018
0.005
0.007
0.058
0.002
0.011
0.018
0.011
0.057
0.012
0.219 (12ꢁ)
0.087 (12ꢁ)
0.024 (3ꢁ)
1.73 (30ꢁ)
0.045 (22ꢁ)
0.294 (16ꢁ)
0.205 (41ꢁ)
0.470 (67ꢁ)
0.748 (13ꢁ)
0.114 (57ꢁ)
N
H2N
H2N
N
8
N
N
9
H
N
N
10
11
O
O
N
N
H
N
a
IC50 values are means of two or more separate determinations.
b
c
The ATP concentration in this experiment is 50
lM.
Fold difference was calculated between enzyme assays.

4140
N. Chen et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4137–4141
Most anilines bearing various substitutions on the phenyl group
a
b, c
HO
OMe
OMe
exhibited a potency and selectivity profile similar to 9. When m-
CF3 was replaced with p-CF3 (Table 5, compound 15), a ꢀ17-fold
Br
O
O
O
decrease in c-Kit potency and > 5 lM activity for KDR was ob-
12
13
served. We therefore envisioned that increasing the steric demand
of substituents in the linear direction may eliminate KDR activity.
Hence, we turned to saturated ring systems (e.g., cyclohexyl) to re-
place the phenyl group and systematically reached out by incorpo-
rating a carbon chain of variable length. When cyclohexylamine
was directly attached (compound 16), the c-Kit activity was dra-
matically reduced, whereas introduction of a methylene linker
(17) led to a 4-fold improvement. Strikingly, the ethylene-linked
analog 18 demonstrated an IC50 value of 35 nM for c-Kit, and
H
H
H
d
OH
N
N
N
N
N
R'
O
O
O
O
H2N
H2N
14
Scheme 2. Reagents and conditions: (a) Pd(OAc)2, Ph3P, Bu3N, CsOAc, H2O, DMF,
CO, 90 °C, 22%; (b) 2,5-diaminopyridine, EDC, HOBt, N,N-diisopropylethylamine; (c)
LiOH, THF, 55% (two steps); (d) R0NH2, PyBop, N,N-diisopropylethylamine, DMF.
was inactive against KDR (up to 25
propylene derivative 19 showed another 4-fold increase in c-Kit
potency. However, the selectivity against p38
improve.
lM). Following this trend, the
lithium hydroxide, gave acid 14 in 55% yield over two steps. The
subsequent coupling step was carried out using PyBop and Hünig’s
base in DMF to provide the final products in good yields.
a and KDR did not
Table 5
Structure–activity relationship: right-hand modification of 9
H2N
N
O
HN
O
HN R'
R0
c-Kita,b IC50
0.007
(
lM)
UT-7 prolifa IC50
0.011
(
lM)
p38aa IC50
0.024 (3ꢁ)
(l
M) (foldc)
KDRa IC50 M) (foldc)
(l
9
15
16
17
0.470 (67ꢁ)
>5 (>42ꢁ)
n/a
CF3
0.120
4.47
1.18
n/a
n/a
n/a
n/a
CF3
0.761
0.143
n/a
18
0.035
0.014
0.181 (5ꢁ)
>25 (>714ꢁ)
19
20
21
0.009
0.077
3.64
0.0003
0.023
n/a
0.0578 (6ꢁ)
0.998 (13ꢁ)
n/a
>5 (>556ꢁ)
>25 (>325ꢁ)
n/a
N
a
IC50 values are means of two or more separate determinations.
b
c
The ATP concentration in this experiment is 50
lM.
Fold difference was calculated between enzyme assays.

N. Chen et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4137–4141
4141
23 nM in the c-Kit-driven UT7 cell-based assay and is significantly
less active against several other kinases (IC50 > 1 M for the
enzyme assay). Compound 20 also showed a good oral PK profile
in rats, and is efficacious in a murine model of mast cell activation
blocking histamine release in vivo with an EC50 of 26 nM.
4000
3000
2000
1000
0
l
EC50 = 290 nM
(free fraction = 26 nM)
Acknowledgment
The authors thank Dr. Alan Allgeier for scaling up intermediate
13 for our SAR studies.
-3
-2
-1
0
1
2
Cmpd conc. in plasma (Log-uM)
References and notes
Figure 1. The correlation of serum histamine levels with compound 20 concentra-
tion in plasma.
1. Yarden, Y.; Kuang, W. J.; Yang-Feng, T.; Coussens, L.; Munemitsu, S.; Dull, T. J.;
Chen, E.; Schlessinger, J.; Francke, U.; Ullrich, A. EMBO J. 1987, 6, 3341.
2. Zsebo, K. M.; Williams, D. A.; Geissler, E. N.; Broudy, V. C.; Martin, F. H.; Atkins,
H. L.; Hsu, R. Y.; Birkett, N. C.; Okino, K. H.; Murdock, D. C.; Jacobsen, F. W.;
Langley, K. E.; Smith, K. A.; Takeishi, T.; Cattanach, B. M.; Galli, S. J.; Suggs, S. V.
Cell 1990, 63, 213.
From this study, we concluded that the ethylene linker provides
an optimal balance of c-Kit potency and off-target activity. We
then studied the effect of the ring size on biological activity and
3. Nocka, K.; Majumder, S.; Chabot, B.; Ray, P.; Cervone, M.; Bernstein, A.; Besmer,
P. Genes Dev. 1989, 3, 816.
4. Bischoff, S. C.; Dahinden, C. A. J. Exp. Med. 1992, 175, 237.
5. Columbo, M.; Horowitz, E. M.; Botana, L. M.; MacGlashan, D. W., Jr.; Bochner, B.
S.; Gillis, S.; Zsebo, K. M.; Galli, S. J.; Lichtenstein, L. M. J. Immunol. 1992, 149,
599.
6. Reber, L.; Silva, C. A.; Frossard, N. Eur. J. Pharmacol. 2006, 533, 327.
7. Jensen, B. M.; Metcalfe, D. D.; Gilfillan, A. M. Inflammation Allergy: Drug Targets
2007, 6, 57.
8. Berlin, A. A.; Lukacs, N. W. Am. J. Respir. Crit. Care Med. 2005, 171, 35.
9. Finotto, S.; Buerke, M.; Lingnau, K.; Schmitt, E.; Galle, P. R.; Neurath, M. F. J.
Allergy Clin. Immunol. 2001, 107, 279.
10. Deininger, M. W. N.; Druker, B. J. Pharmacol. Rev. 2003, 55, 401.
11. Joensuu, H.; Roberts, P. J.; Sarlomo-Rikala, M.; Anderson, L. C.; Tervahartiala, P.;
Tuveson, D.; Silberman, S. L.; Capdeville, R.; Dimitrijevic, S.; Druker, B.;
Demetri, G. D. N. Engl. J. Med. 2001, 344, 1052.
found that cyclopentyl (20) resulted in good c-Kit potency (IC50
77 nM for the enzyme and 23 nM for the UT7 cell) and excellent
selectivity against the other kinases (IC50: p38 , 1.0 M; KDR,
>25 M; Lck, 1.9 M; Src, 5.0 M). Substituting the cyclopentyl
:
a
l
l
l
l
group with a basic pyrrolidine (21) resulted in loss of c-Kit potency.
Based on the encouraging in vitro kinase activity profile, we
studied the PK properties of compound 20. When dosed iv, the
compound had a clearance of 4.1 L/h/kg and a half life of 4.4 h. Fol-
lowing oral administration (10 mg/kg), it exhibited a Cmax of
518 ng/mL and AUC of 1922 ng*h/mL, with an estimated oral bio-
availability of 78%. The rat and mouse plasma protein binding were
determined by ultracentrifugation to be 82% and 91%, respectively.
The PK profile of 20 was deemed sufficient to conduct a proof-
of-concept study in vivo. For this, compound 20 was tested in an in
vivo murine model of mast cell activation and systemic anaphy-
laxis. Stem cell factor, when administered systemically, activates
mast cells, and provides a physiologically relevant and clear mech-
anistic assessment of c-Kit inhibitors.19 Mice20 were dosed with 20
orally 1 h before an intravenous injection of SCF.21 Fifteen minutes
after SCF treatment, the mice were euthanized by CO2 inhalation
and blood was collected by cardiac puncture for histamine mea-
surement and PK analysis. SCF-induced serum histamine was
quantified, and ED50 values were calculated from a dose-response
curve (Fig. 1). From this study,22 we concluded that compound
20 dose-dependently inhibited SCF-induced histamine release
with an EC50 value of 26 nM (free fraction), similar to the UT7
12. Van Oosterom, A. T.; Judson, I.; Verweij, J.; Stroobants, S.; Donato; di Paola, E.;
Dimitrijevic, S.; Martens, M.; Webb, A.; Sciot, R.; Van Glabbeke, M.; Silberman,
S.; Nielsen, O. S. Lancet 2001, 358, 1421.
13. Paniagua, R. T.; Sharpe, O.; Ho, P. P.; Chan, S. M.; Chang, A.; Higgins, J. P.;
Tomooka, B. H.; Thomas, F. M.; Song, J. J.; Goodman, S. B.; Lee, D. M.; Genovese,
M. C.; Utz, P. J.; Steinman, L.; Robinson, W. H. J. Clin. Invest. 2006, 116, 2633.
14. Juurikivi, A.; Sandler, C.; Lindstedt, K. A.; Kovanen, P. T.; Juutilainen, T.;
Leskinen, M. J.; Mäki, T.; Eklund, K. K. Ann. Rheum. Dis. 2005, 64, 1126.
15. Adams, J. L.; Badger, A. M.; Kumar, S.; Lee, J. C. Prog. Med. Chem. 2001, 38, 1.
16. 1 was dosed intravenously in rat at 5 mg/kg. The plasma, bile and urine
samples were collected and analyzed for metabolites at time points of 1, 4, and
8 h.
17. UT-7 is a factor dependent human megakaryoblastic leukemia cell line that
carries wild type c-Kit receptor. The purpose of this assay is to test the general
anti-proliferative effect of small molecule compounds on SCF-stimulated UT-7
cells.
18. Mol, C. D.; Dougan, D. R.; Schneider, T. R.; Skene, R. J.; Kraus, M. L.; Scheibe, D.
N.; Snell, G. P.; Zou, H.; Sang, B.-C.; Wilson, K. P. J. Biol. Chem. 2004, 279, 31655.
19. Costa, J. J.; Demetri, G. D.; Harrist, T. J.; Dvorak, A. M.; Hayes, D. F.; Merica, E. A.;
Menchaca, D. M.; Gringeri, A. J.; Schwartz, L. B.; Galli, S. J. J. Exp. Med. 1996, 183,
2681.
20. C57 Bl/6 female mice were obtained from Charles River Laboratories and were
housed under pathogen-free conditions at Amgen animal facility in Thousand
Oaks. 10–15 weeks old female mice were used for experiments.
21. SCF was obtained from Protein Science at Amgen Inc. Lot # was 08032,
0.95 mg/ml in PBS. ELISA kit for histamine measurement was obtained from
Oxford Biomedical Research (EA31).
cell-based IC50
.
In summary, we have identified
a
potent and selective
small-molecule c-Kit inhibitor through a SAR study based on the
screening hit 1 of our kinase-preferred compound collection.
Optimization for metabolic stability, PK, and potency yielded com-
pound 9. To ensure good safety margin from angiogenesis and
22. Gleevec was also tested in the SCF challenge model. Mice were dosed with
100 mg/kg of compound po 1 h prior to the SCF injection. Histamine release
was inhibited by 88%.
inflammation pathways, we further optimized KDR and p38
a
kinase selectivity to yield 20. Compound 20 exhibited an IC50 of