Discovery of INCB3284, a potent, selective, and orally bioavailable hCCR2 antagonist

Article abstract of DOI:10.1021/ml200030q

We report the identification of 13 (INCB3284) as a potent human CCR2 (hCCR2) antagonist. INCB3284 exhibited an IC₅₀ of 3.7 nM in antagonism of monocyte chemoattractant protein-1 binding to hCCR2, an IC ₅₀ of 4.7 nM in antagonism of c

Full text of DOI:10.1021/ml200030q

LETTER
pubs.acs.org/acsmedchemlett
Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable
hCCR2 Antagonist
Chu-Biao Xue,* Hao Feng, Ganfeng Cao, Taisheng Huang, Joseph Glenn, Rajan Anand, David Meloni,
Ke Zhang, Lingquan Kong, Anlai Wang, Yingxin Zhang, Changsheng Zheng, Michael Xia, Lihua Chen,
Hiroyuki Tanaka, Qi Han, D. J. Robinson, Dilip Modi, Lou Storace, Lixin Shao, Vaqar Sharief, Mei Li,
Laurine G. Galya, Maryanne Covington, Peggy Scherle, Sharon Diamond, Tom Emm, Swamy Yeleswaram,
Nancy Contel, Kris Vaddi, Robert Newton, Greg Hollis, Steven Friedman, and Brian Metcalf
Incyte Corporation, Experimental Station E336, Wilmington, Delaware 19880, United States
S Supporting Information
b
ABSTRACT: We report the identification of 13 (INCB3284) as a potent
human CCR2 (hCCR2) antagonist. INCB3284 exhibited an IC50 of 3.7 nM
in antagonism of monocyte chemoattractant protein-1 binding to hCCR2,
an IC50 of 4.7 nM in antagonism of chemotaxis activity, an IC50 of 84 μM in
inhibition of the hERG potassium current, a free fraction of 58% in protein binding, high selectivity over other chemokine receptors
and G-protein-coupled receptors, and acceptable oral bioavailability in rodents and primates. In human clinical trials, INCB3284
exhibited a pharmacokinetic profile suitable for once-a-day dosing (T1/2 = 15 h).
KEYWORDS: CCR2, chemokine, antagonist, hERG, oral absorption
acrophages, which are derived from monocytes, a subset of
leukocytes, are well-characterized mediators of tissue de-
over other homologous chemokine receptors, and its good
pharmacokinetics profile but was not suitable as a clinical
candidate due to its moderate hERG activity (IC50 = 13 μM)
as assessed using a dofetilide binding assay, which did not meet
our criteria in hERG binding activity. In addition, INCB3344 was
an inhibitor of CYP3A4.
M
struction. These cells can be activated to secrete proinflamma-
tory cytokines such as TNFR and IL-1β, tissue-degrading
enzymes such as MMPs, and other chemokines that mediate
the influx of other inflammatory cells.1 Excessive recruitment of
these cells to sites of inflammation leads to significant tissue
destruction and contributes to the morbidity of chronic inflam-
matory and autoimmune diseases. The trafficking of monocytes/
macrophages to sites of inflammation is believed to be predo-
minantly mediated by monocyte chemoattractant protein-1
(MCP-1, CCL2) through interaction with its specific receptor,
CCR2, which is a member of the super family of seven-trans-
membrane G-protein-coupled receptors (GPCRs) and is pre-
dominantly expressed on monocytes. Binding of MCP-1 to
CCR2 induces chemotaxis, resulting in directed migration of
monocytes/macrophages to disease sites where MCP-1 expres-
sion is elevated.2 Studies in rodent models have demonstrated
the critical role of MCP-1/CCR2 in inflammatory and auto-
immune diseases and strongly suggest that CCR2 is an attractive
therapeutic target.3 As a result, inhibition of CCR2 has emerged
as a novel therapeutic approach for pharmaceutical research, and
a number of potent small molecule CCR2 antagonists have been
identified.4À10
In the course of SAR studies on the INCB3344 series in an
attempt to identify a clinical candidate, we discovered that
removal of the ethoxy at the 3-position on the pyrrolidine in
the INCB3344 series as in 1 (Figure 2) resulted in a significant
loss in mCCR2 activity but retained the hCCR2 activity as in 2
(Figure 2). An R configuration at the 3-position on the pyrro-
lidine as shown in 2 is required for activity as the S enantiomer of
2 displayed an IC50 of >1 μM in hCCR2 MCP-1 assay. Although
this des-ethoxy series is not superior to the INCB3344 series by
comparison of 2 with 1 in hCCR2 activity and hERG binding
activity, the 1,3-disubstituted pyrrolidine core in this series offers
an advantage over the 1,3,4-trisubstituted pyrrolidine core in the
INCB3344 series from a synthetic point of view as the former
core structure, (R)-3-aminopyrrolidine, has only one chiral
center and is commercially available, while the latter core
structure, trans-4-amino-3-ethoxypyrrolidine, has two chiral cen-
ters and is not commercially available. These considerations
prompted us to take 2 as a lead compound for modifications.
Like INCB3344, 2 exhibited moderate dofetilide hERG bind-
ing activity with an IC50 of 13.2 μM, which exceeded our criteria.
Because 2 has a cLogP of 4.08, we reasoned that the moderate
hERG binding activity of 2 could be ascribed to the hydrophobicity
We have reported the discovery of a novel series of CCR2
antagonists through rational design.10 Our structureÀactivity
relationship (SAR) studies on that series of compounds led to the
identification of INCB3344 (Figure 1), a potent, selective, and
orally bioavailable antagonist of human and murine CCR2
(hCCR2 and mCCR2). INCB3344 has been used as a tool
compound for target validation in rodent models because of its
potent inhibitory activity toward murine CCR2, its selectivity
Received: February 2, 2011
Accepted: March 27, 2011
Published: March 31, 2011
r
2011 American Chemical Society
450
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LETTER
of the molecule. While the impact on CCR2 binding could not be
predicted, if the cLogP is decreased, it is likely that the hERG
activity could be reduced,11,12 The high cLogP of 2 is attributed
to the two hydrophobic phenyl rings on the left-hand and right-
hand sides. Our previous SAR studies had demonstrated that the
trifluoromethylphenyl residue on the right-hand side is critical to
the CCR2 binding affinity. For this reason, we targeted the
phenyl residue on the left-hand side for modifications in an
attempt to increase the polarity of the molecule. cLogP calcula-
tions revealed that the cLogP of 2 can be dramatically lowered
down if the phenyl residue on the left-hand side is replaced with a
heteroaromatic ring such as a pyridyl (cLogP = 2.09). Thus, SAR
studies at the 4-position of the cyclohexyl were carried out by
replacing the phenyl ring with different heteroaryl rings. The
heterocycles that we investigated include pyridine, pyrimidine,
pyridazine, and pyrazine. As shown in Table 1, the three pyridyl
regioisomers 3À5 displayed similar hCCR2 activity and, more
importantly, were very potent hCCR2 antagonists with low
nanomolar activities in the MCP-1 and chemotaxis assays,
demonstrating the tolerability of a polar heteroaromatic ring at
the 4-position of the cyclohexyl ring for hCCR2 activity. As
expected, these polar analogues exhibited weak hERG binding
activity, with an IC50 of >30 μM, meeting our criteria for
advancing to mouse pharmacokinetic (PK) screens. When
administered orally to mice, the pyridin-2-yl analogue 3 was well
Figure 1. Structure of INCB3344.
absorbed, with a high AUC of 2812 nM h at a dose of 10 mg/kg,
3
while the pyridin-3-yl analogue 4 and the pyridine-4-yl analogue
5 exhibited very low blood levels at the same dose. The excellent
PK profile of 3 prompted us to conduct a patch clamp assay.
Disappointingly, it exhibited 57% inhibition of the hERG potas-
sium current at a concentration of 10 μM (IC50 < 10 μM), which
did not meet our criteria (IC50 > 10 μM) in the hERG patch
clamp activity for a clinical candidate.
By comparison with the pyridyl analogues 3À5, the two-
nitrogen-containing heteroaryl analogues 6À11 displayed
slightly weaker hCCR2 activity in both the MCP-1 and the
chemotaxis assays (Table 1). The pyrimidin-5-yl analogue 8 was
not potent enough in CCR2 activity, while the pyrimidin-2-yl (6)
and pyrazin-2-yl (11) analogues were just potent enough to meet
Figure 2
Table 1. Heteroaryl Analogues 3À14
IC50 (nM)
compd
R
MCP-1a,b
CTXa,c
hERG bindingd
patch clamp at 10 μMe (%)
mouse oral AUCf (nM h)
3
3
4
pyridin-2-yl
3.2 (10)
2.6 (16)
4.3 (2)
3.2 (8)
3.9 (12)
3.0 (2)
>30
>30
>30
>30
>30
57
2812
50
pyridin-3-yl
5
pyridin-4-yl
100
1442
930
6
pyrimidin-2-yl
pyrimidin-4-yl
pyrimidin-5-yl
pyridazin-3-yl
pyridazin-4-yl
pyrazin-2-yl
10.3 (10)
7.8 (22)
14 (2)
9.3 (9)
25
7
7
7.5 (30)
20 (2)
8
9
7.3 (8)
5.8 (6)
>30
>30
>30
>30
>30
>30
155
80
10
11
12
13
14
4.9 (4)
7.2 (2)
10.9 (22)
2.4 (2)
10.4 (30)
5.6 (2)
7
1550
127
617
287
6-Me-pyridin-3-yl
6-MeO-pyridin-3-yl
6-EtO-pyridin-3-yl
3.7 (30)
4.7 (30)
7.7
3.2 (10)
2.7 (6)
a Averaged values were given from numbers of determinations indicated in parentheses. Standard deviations are within 30% of the measured value. For
assay protocols, see ref 10. b Antagonism of MCP-1 binding to hCCR2. c Antagonism of chemotaxis activity. d Dofetilide hERG binding activity from two
determinations. e Inhibition of hERG potassium current at 10 μM from single determination of patch clamp assay. f Normalized mouse oral AUC at 10
mg/kg from cassette studies (three animals each cassette).
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Table 2. Pharmacokinetic Parameters of INCB003284
rats
dogs
monkeys
chimpanzees
iv (two animals in each species)
po (two animals in each species)
dose (mg/kg)
CL (L/h/kg)
Vss
5
5
5
1
3.4 ( 0.3
10.5 ( 0.5
2.8 ( 0.2
10
0.57 ( 0.02
1.6 ( 0.1
3.5 ( 0.1
30
0.82 ( 0.04
0.7 ( 0.2
2.2 ( 0.3
30
0.35 ( 0.01
0.94 ( 0.03
3.8 ( 0.2
4
T1/2 (h)
dose (mg/kg)
Cmax (nM)
Tmax (h)
573 ( 120
4.0 ( 0.6
3657 ( 560
2.9 ( 0.3
20
7813 ( 560
1.5 ( 0.5
33,283 ( 1215
3.3 ( 0.7
31
2633 ( 320
1.5 ( 0.3
9078 ( 980
5.1 ( 0.5
13
1122 ( 750
2.0 ( 0
4942 ( 3388
5.3 ( 1.0
23
AUC (nM h)
3
T1/2 (h)
F %
our criteria (IC50 < 10 nM in MCP-1 and chemotaxis assays) for
Given its superior profile in a combination of hCCR2 potency,
mouse oral absorption, and hERG patch clamp activity, com-
pound 13 (INCB3284) was selected for further in vitro and
in vivo evaluations. INCB3284 is a potent hCCR2 antagonist
with IC50 values of 3.7 nM in antagonism of MCP-1 binding to
hCCR2 and 4.7 nM in antagonism of chemotaxis activity. It
potently inhibited CCR2-mediated signaling events such as
intracellular calcium mobilization and ERK phosphorylation
with IC50 values of 6 and 2.6 nM, respectively. Cerep screens
revealed that INCB3284 is a selective CCR2 inhibitor, showing
no significant inhibitory activity at a concentration of 1 μM when
tested against a panel of >50 ion channels, transporters, chemo-
kine receptors including CCR1, CCR3, CCR5, CXCR3, and
CXCR5, and additional GPCRs. In the hERG patch clamp assay,
INCB3284 inhibited hERG potassium current with an IC50 of
84 μM. In protein binding, INCB3284 had a high free fraction
(58%) in human serum at concentrations of 1 and 10 μM. When
incubated with human liver microsomes, INCB3284 exhibited a
moderate intrinsic clearance. However, studies with recombinant
CYP isozymes showed that INCB003284 is a substrate for CYP3A4
and CYP2D6. Recombinant CYP3A4 metabolized INCB003284 at
the CÀN bond between the pyrrolidine nitrogen and the cyclohexyl
carbon to its N-dealkylated metabolite, while recombinant CYP2D6
metabolized INCB3284 at the CÀO bond of the methoxy group
between the methyl and the 6-hydroxypyridyl oxygen to the des-
methyl metabolite. When INCB3284 was incubated with human S9
with or without NADPH and the cofactor glutathione, no glutathione
adducts were detected. INCB003284 is not a CYP inhibitor, with
IC50 values of >25 μM against five major CYP isozymes CYP1A2,
CYP2C9, CYP2C19, CYP2D6, and CYP3A4. INCB3284 is not a
CYP inducer at concentrations up to 10 μM as measured in the
luminometric luciferase assay.
The pharmacokinetics of INCB3284 was investigated in rats,
dogs, cynomolgus monkeys, and chimpanzees (Table 2). Follow-
ing iv administration of INCB3284, the total systemic clearance
was high in rats but low in dogs, cynomolgus monkeys, and
chimpanzees. The apparent steady state volume of distribution
(Vss) followed the same trend as in clearance, with high Vss in rats
and low Vss in dogs, cynomolgus monkeys, and chimpanzees. As a
result, INCB003284 had a short to moderate half-life after iv
administration ranging from 2.2 to 3.8 h. When administered
orally, a similarhalf-life was observed in rats and dogs, whileslightly
longer half-life was achieved in monkeys and chimpanzees. The
oral bioavailability ranged from 13% in cynomolgus monkeys to
31% in dogs.
further profiling. Because compounds 6 and 7 and 9À11
exhibited weak dofetilide hERG binding activity (IC50
>
30 μM), they were subjected to PK screens in mice. High plasma
levels were observed for the two pyrimidine compounds 6 and 7
and the pyrazine compound 11, while the two pyridazine
compounds 9 and 10 were poorly absorbed in mice. When
subjected to patch clamp assays, strikingly, 6, 7, and 11 exhibited
weak inhibition of the hERG potassium current. Of special note
were 7 and 11, which displayed only 7% inhibition at a
concentration of 10 μM in the hERG patch clamp assay,
representing the first two compounds from this series with good
oral absorption in mice concurrent with weak inhibition (<10%
at 10 μM) of the hERG potassium current.
To obtain an insight into the huge difference in oral exposure
between the 2-pyridyl analogue 3 and the 3-pyridyl analogue 4,
ADME studies were carried out on 3 and 4 and revealed that 4
had a much lower permeability and more profound N-oxidation
at the pyridyl nitrogen than 3 (data not shown). We reasoned
that these differences could be ascribed to the steric effect on the
pyridyl nitrogen. The pyridyl nitrogen in 3 is sterically shielded
by the cyclohexyl residue. In contrast, the pyridyl nitrogen in 4 is
more exposed with a likely impact on transcellular permeation
and an increased susceptibility to oxidation as compared to the
2-pyridyl nitrogen. To shield the pyridyl nitrogen in 4 from
solvation and oxidation, we introduced a methyl group at the
6-position of the pyridyl to provide 12. This modification
maintained the hCCR2 potency and the weak hERG binding
activity but resulted in a little improvement in mouse oral
exposure, with only 2.5-fold enhancement in the area under
the curve (AUC). It is likely that the methyl group is not bulky
enough to shield the pyridyl nitrogen from solvation and oxida-
tion. In contrast, introduction of a methoxy group at the
6-position of the pyridyl in 4 to provide a less basic pyridyl
residue not only maintained the hCCR2 potency and the weak
dofetilide binding activity but improved the oral exposure from
an AUC of 50 nM h at 10 mg/kg in 4 to an AUC of 617 nM h at
3
3
the same dose in 13, a 12-fold enhancement. When subjected to a
patch clamp assay, remarkably, compound 13 exhibited only
7.7% inhibition of the hERG potassium current at a concentra-
tion of 10 μM, representing another potent CCR2 antagonist
with acceptable oral exposure in mice concurrent with weak
hERG activity (<10% at 10 μM) in the patch clamp assay.
Increasing the length of the alkoxy group in 13 by replacing the
methoxy with ethoxy (14) maintained the hCCR2 activity but
led to a lower blood level (AUC = 287 nM h at 10 mg/kg)
in mice.
As outlined in Scheme 1, this series of compounds were
synthesized starting from the commercially available (R)-1-
3
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Scheme 1. Synthesis of Compounds 3À14a
Scheme 3. Synthesis of INCB3284 Bismesylatea
a Reagents and conditions: (a) H2, Pd/C, Al2O3, CH2Cl2, trans:cis = 4:1.
(b) 2 Â MeSO3H, EtOH, EtOAc, trans:cis = 98:2, 60% yield. (c) NaOH,
CH2Cl2. (d) 2 Â MeSO3H, EtOH, EtOAc, trans:cis = 99.8:0.2,
90% yield.
4-position on cyclohexyl trans to the pyrrolidin-1-yl residue at
the 1-position on the cyclohexyl and were the active isomers
3À14. The cis isomers were inactive (<50% inhibition) at a
concentration of 1 μM in the MCP-1 assay. The stereochemistry
at the cyclohexyl was further confirmed by X-ray crystallography
on the tartaric acid salt of 3. The X-ray crystal structure revealed
that the cyclohexyl assumes a chair conformation with pyridin-2-
yl at the equatorial position and hydroxyl and pyrrolidin-1-yl at
the axial positions. There is no intramolecular hydrogen bond
formed between the hydroxyl proton and the pyridyl nitrogen in
the crystal structure as the hydroxyl group and the pyridyl
nitrogen are situated at the opposite directions on the cyclo-
hexane plane.
a Reagents and conditions: (a) Isobutyl chloroformate, NMM, THF,
76%. (b) H2, Pd(OH)2, MeOH, 95%. (c) Na(OAc)3BH, THF.
Scheme 2. Synthesis of Ketonesa
A general route to the synthesis of the ketone intermediate 19
is presented in Scheme 2A. Lithiation of a (un)substituted
bromoheterocycle (R-Br, 20) using n-butyl lithium at À78 °C
followed by addition of 1,4-cyclohexanedione mono-ethylene
ketal 21 gave rise to the ketal intermediate 22. Treatment of
22 with aqueous HCl converted the ketal to the corresponding
ketone 19. For some of the heterocycles, bromine-substituted
heterocycles were not commercially available or lithiation of
bromoheterocycles did not produce the desired products. For
these reasons, alternative synthetic routes were developed as
shown in Scheme 2BÀD. The 4-hydroxy-4-(pyrimidin-4-yl)-
cyclohexanone 19a and 4-hydroxy-4-(pyrazin-2-yl)cyclohexanone
19b were prepared from 5-bromopyrimidine 23 (Scheme 2B)
and 2,6-dichloropyrazine 25 (Scheme 2C), respectively. Treat-
ment of 23 or 25 with lithium diisopropylamide (LDA) followed
by quenching with 21 provided the bromine-containing ketal 24
or the chlorine-containing ketal 26. Hydrogenation in the
presence of triethylamine to remove the bromine in 24 or
chlorine in 26 followed by acid treatment to hydrolyze the ketal
furnished the ketones 19a and 19b. The two pyridazine deriva-
tives 19c and 19d were prepared from pyridazine 27 (Scheme 2D).
Treatment of 27 with lithium 2,2,6,6-tetramethylpiperidinide
followed by addition of 21 gave rise to a mixture of two
regioisomers 28a and 28b. After separation by chromatography,
the two isomers were treated with acid to provide the corre-
sponding ketones 19c and 19d.
a Reagents and conditions: (a) n-Butyllithium, THF, À78 °C. (b) (1) 2
N HCl, H2O, THF; (2) Na2CO3, pH 8. (c) LDA, THF, À78 °C, 21,
20% yield for 24, 25% yield for 26. (d) H2, Pd/C, Et3N, MeOH. (e)
Lithium 2,2,6,6-tetramethylpiperidinide, THF, À78 °C, 21, 12% yield
for 28a, 10% yield for 28b.
benzyl-3-aminopyrrolidine 15. Coupling of 15 with the glycine
derivative 16 using isobutyl chloroformate followed by removal
of the benzyl group by hydrogenation produced the pyrrolidine
intermediate 18. Reductive amination of 18 with 4,4-disubstitut-
ed cyclohexanone 19 using sodium triacetoxyborohydride as the
reducing agent provided the final compounds as a mixture of two
isomers with a ratio of about 3:2. The two isomers were separated
by silica gel chromatography. The major isomers were character-
ized by NMR to be trans isomers with the hydroxyl at the
The reductive amination to produce INCB3284 from its
corresponding ketone 19e and the pyrrolidine intermediate 18
have been investigated extensively. It was discovered that the 3:2
ratio of the trans isomer (INCB3284) versus the cis isomer
obtained using sodium triacetoxyborohydride as the reducing agent
could be improved to 4:1 when the reductive amination was
conducted by hydrogenation in the presence of aluminum oxide
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using palladium on carbon as the catalyst. Without chromatography,
the trans isomer (INCB3284) could be enriched to a ratio of
trans:cis = 98:2 by crystallization of the crude product with
methanesulfonic acid. The crystalline salt obtained was basified
with NaOH, and the resulting free base was subjected to another
crystallization using methanesulfonic acid, affording pure crystal-
line salt of INCB3284 bismesylate (Scheme 3).
In summary, we took 2 as a lead compound for modifications
in an attempt to optimize its moderate hERG activity. SAR
studies were carried out on the left-hand side in 2 by replacing the
phenyl ring with a variety of heteroaromatic rings, leading to the
identification of 13 (INCB3284). INCB3284 exhibited a ba-
lanced profile in potent hCCR2 activity, high selectivity, weak
hERG activity, high free fraction in protein binding, and accep-
table oral bioavailability in rats, dogs, cynomolgus monkeys,
and chimpanzees, meeting our criteria for a clinical candidate.
The tolerated safety profile from GLP toxicology studies in
rodents and primates justified its advancement into human
clinical trials. Phase I and phase II clinical studies revealed that
INCB3284 exhibited a PK profile suitable for once-a-day dosing
(T1/2 = 15 h).
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures for
b
the synthesis of 13, characterization data for 1À14, and X-ray
crystal structure of the tartaric acid salt of 3. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: 302-498-6706. Fax: 302-425-2750. E-mail: cxue@
incyte.com.
’ ACKNOWLEDGMENT
We thank Lynn Leffet, Karen Gallagher, Patricia Feldman,
Bitao Zhao, Yanlong Li, Robert Collins, Xiaomei Gu, and Peng
Pan for technical assistance.
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