Discovery of INCB8761/PF-4136309, a potent, selective, and orally bioavailable CCR2 antagonist

Article abstract of DOI:10.1021/ml200199c

We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high sel

Full text of DOI:10.1021/ml200199c

Letter
pubs.acs.org/acsmedchemlett
Discovery of INCB8761/PF-4136309, a Potent, Selective, and Orally
Bioavailable CCR2 Antagonist
Chu-Biao Xue,*,† Anlai Wang,† Qi Han,† Yingxin Zhang,† Ganfeng Cao,† Hao Feng,† Taisheng Huang,†
Changsheng Zheng,† Michael Xia,† Ke Zhang,† Lingquan Kong,† Joseph Glenn,† Rajan Anand,†
David Meloni,† D. J. Robinson,† Lixin Shao,† Lou Storace,† Mei Li,† Robert O. Hughes,‡ Rajesh Devraj,‡
Philip A. Morton,‡ D. Joseph Rogier,‡ Maryanne Covington,† Peggy Scherle,† Sharon Diamond,†
Tom Emm,† Swamy Yeleswaram,† Nancy Contel,† Kris Vaddi,† Robert Newton,† Greg Hollis,†
and Brian Metcalf†
†Incyte Corporation, Experimental Station E336, Wilmington, Delaware 19880, United States
‡Pfizer Global Research and Development, Chesterfield Parkway West, St. Louis, Missouri 63017, United States
S
* Supporting Information
ABSTRACT: We report the discovery of a new (S)-3-aminopyrrolidine
series of CCR2 antagonists. Structure−activity relationship studies on this
new series led to the identification of 17 (INCB8761/PF-4136309) that
exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG
activity, and an excellent in vitro and in vivo ADMET profile. INCB8761/
PF-4136309 has entered human clinical trials.
KEYWORDS: CCR2, chemokine, antagonist, hERG
CR2 is a chemokine receptor, a member of the super
Cfamily of seven-transmembrane G-protein-coupled recep-
tors (GPCRs), and is predominantly expressed on monocytes.
Monocyte chemoattractant protein-1 (MCP-1, CCL2) is a
specific ligand for CCR2. Binding of MCP-1 to CCR2 induces
chemotaxis, resulting in directed migration of monocytes/
macrophages to disease sites where MCP-1 expression is
elevated. Because macrophages are well-characterized mediators
of tissue destruction, accumulation of macrophages at disease
sites could lead to morbidity and deterioration of chronic
inflammatory and autoimmune diseases.1 Studies in rodent
models have demonstrated the critical role of MCP-1/CCR2 in
inflammatory and autoimmune diseases and strongly suggest
that CCR2 is an attractive therapeutic target.2 As a result,
Figure 1.
antagonism of CCR2 has emerged as a novel therapeutic
approach for pharmaceutical research, and a number of potent
(S)-3-aminopyrrolidine derivative 2 utilizing 4-phenylcyclohex-
small molecule CCR2 antagonists have been identified.3−11
yl as the left-hand side moiety (Figure 2). As drawn in 1 and 2
We have reported the discovery of an (R)-3-amino-
(Figure 2), the stereochemistry at the cyclohexyl was presumed
pyrrolidine series of CCR2 antagonists and the identification
to be cis by analogy to that in the INCB3344 and INCB3284
of a clinical compound INCB3284 (Figure 1) from that
series.9,11 This was later confirmed by the X-ray crystal
structure of 17 (vide infra). In contrast to the INCB3284
series.11 As a follow-up in our CCR2 project, we tried to
identify a second generation of CCR2 antagonist with structural
series where an R configuration at the pyrrolidine is critical to
diversity and a better overall profile. On the basis of molecular
CCR2 activity, 1 with an R configuration is a very weak CCR2
modeling, we proposed that the connections to the (R)-3-
antagonist with an IC50 of 860 nM in antagonism of MCP-1
binding to human CCR2 (hCCR2), while 2 with an S
aminopyrrolidine core of the left-hand side functional group (4-
hydroxy-4-heteroarylcyclohexyl) and the right-hand side func-
tional group (3-trifluoromethylbenzoylaminoacetyl) in the
INCB3284 series could be reversed to provide a new series
of compounds as shown in I (Figure 1). To test this hypothesis,
we synthesized the (R)-3-aminopyrrolidine derivative 1 and
Received: August 16, 2011
Accepted: October 5, 2011
Published: October 5, 2011
© 2011 American Chemical Society
913
dx.doi.org/10.1021/ml200199c|ACS Med. Chem. Lett. 2011, 2, 913−918

ACS Medicinal Chemistry Letters
Letter
hand side moiety and the right-hand side moiety in INCB3284
reflects the changes around the pyrrolidine ring from a
secondary amide, a tertiary amine, and an R configuration in
INCB3284 to a tertiary amide, a secondary amine, and an S
configuration in 5, respectively, as the left-hand side moiety and
the right-hand side moiety in both compounds are the same.
However, it is likely that these changes may cause a twisted
orientation of the 4-hydroxy-4-(6-methoxy-2-pyridyl)cyclohexyl
moiety on the left-hand side that is now not an optimal residue
for effective interaction with the receptor. Thus, we continued
to explore other heteroaryls. Removal of the methoxy group in
5 afforded the 3-pyridyl analogue 6 that is not as active as 5.
Strikingly, replacement of the 3-pyridyl in 6 with 2-pyridyl
improved the binding affinity from an IC50 of 126 nM for 6 to
an IC50 of 11 nM for 7, a 12-fold enhancement. The 12-fold
improvement in binding affinity of 7 over 6 is not merely the
result of polarity alteration from the barely exposed 3-pyridyl
nitrogen in 6 to the sterically shielded 2-pyridyl nitrogen in 7 as
7 is 6-fold more active than the more hydrophobic phenyl
analogue 4. It is likely that the 2-pyridyl nitrogen places the 2-
pyridyl residue in a favorable orientation for more effective
interaction with the receptor. Attempts to add one more
nitrogen at the 3-position within the 2-pyridyl ring in 7 to
provide the more polar 2-pyrimidinyl (8) resulted in a 6-fold
loss in binding affinity. However, the binding affinity is less
affected when the 2-pyridyl in 7 is replaced with 2-thiazolyl (9).
Because the 2-pyridyl is superior to other heterocycles at the
4-position of cyclohexyl, 7 was taken forward for further SAR
exploration. To improve the CCR2 activity of 7, we considered
extending the left-hand side moiety by substitution on the 2-
pyridyl ring. A simple methyl group substitution was first
attempted (Table 1). Substitution at 4-position (10) or 6-
position (11) resulted in about 28- and 5-fold loss, respectively,
in binding affinity while substitution at 5-position (12) slightly
improved the binding affinity. More importantly, the methyl
group in 12 improved the chemotaxis activity from an IC50 of
52 nM in 7 to an IC50 of 15 nM in 12. These results
demonstrated that substitution at the 4- or 6-position is
detrimental, while CCR2 binding affinity and especially
chemotaxis activity can be improved by attachment of an
extra group at the 5-position of the 2-pyridyl.
Although 7 and 12 did not meet our criteria in CCR2
activity, they were subjected to dofetilide binding assay12 and
patch clamp assay to understand the hERG activity of this series
of compounds (Table 2). Compound 7 was a weak hERG
inhibitor, displaying an IC50 of >30 μM in the dofetilide assay
and 34% inhibition at 10 μM in the patch clamp assay. In
contrast, 12 was a potent hERG inhibitor, exhibiting an IC50 of
24 μM in the dofetilide assay and 71% inhibition at 10 μM in
the patch clamp assay. These results prompted us to investigate
polar heteroaryl groups at the 5-position of the 2-pyridyl in 7 in
an attempt to improve the CCR2 activity while concurrently
minimizing the hERG activity.
As shown in Table 2, attachment of 3-pyridyl (13) or 4-
pyridyl (14) at the 5-position of the 2-pyridyl in 7 had little
effect on the CCR2 binding affinity but remarkably improved
the chemotaxis activity by 10- and 20-fold, respectively.
Surprisingly, these polar groups also increased the hERG
activity. Compounds 13 and 14 were more potent than 7 in the
dofetilide assay. For this reason, attempts were made to further
increase the polarity of the left-hand side moiety by replacing
the distal pyridyl with 2-heteroatom containing heterocycles
(15−19). The 5-pyrimidinyl analogue 15 was not potent
Figure 2.
configuration is 25-fold more potent than 1, with an IC50 of 35
nM. Methylation of the secondary basic amine in 2 resulted in a
slight loss in binding affinity (3, IC50 = 84 nM).
Encouraged by the decent binding affinity of 2, structure−
activity relationship (SAR) studies were initiated at the 4-
position of cyclohexyl on the left-hand side (Table 1). Our
Table 1. Identification of Aryl/Heteroaryl Ring at the 4-
Position of Cyclohexyl
a
CCR2, IC50 (nM)
b
c
compd
R
binding
CTX
4
5
phenyl
65 (2)
95 (2)
6-methoxy-3-
pyridyl
6
7
3-pyridyl
126 (2)
11 (8)
66 (2)
18 (2)
305 (2)
2-pyridyl
52 (8)
8
2-pyrimidinyl
2-thiazolyl
9
10
4-methyl-2-
pyridyl
11
12
6-methyl-2-
pyridyl
51 (2)
5-methyl-2-
pyridyl
6.9 (12)
15 (12)
a
Numbers in parentheses represent numbers of determinations.
Standard deviations were less than 30% of the measured value. For
b
assay protocols, see ref 9. Antagonism of MCP-1 binding to hCCR2.
c
Antagonism of chemotaxis activity.
previous SAR studies in the INCB3344 series9 and INCB3284
series11 have demonstrated that a hydroxyl group and a
heteroaryl at the 4-position of cyclohexyl were consistent with
weak hERG activity and low intrinsic clearance. Thus, we first
added a hydroxyl at the 4-position of cyclohexyl in 2 to provide
analogue 4. This resulted in a slight loss in CCR2 binding
affinity (IC50 = 65 nM). We next replaced the phenyl at the 4-
position of cyclohexyl in 4 with different heteroaryls.
Disappointingly, replacement of the phenyl at the 4-position
of cyclohexyl in 4 with 6-methoxy-3-pyridyl, the left-hand side
heteroaryl in INCB3284, provided analogue 5, which is not as
potent as 4 and is 26-fold weaker than INCB3284 in binding
affinity. The 26-fold loss in binding affinity resulting from
reversing the connections to the 3-aminopyrrolidine of the left-
914
dx.doi.org/10.1021/ml200199c|ACS Med. Chem. Lett. 2011, 2, 913−918

ACS Medicinal Chemistry Letters
Letter
a
Table 2. Modification at the 5-Position on the 2-Pyridyl
CCR2, IC50 (nM)
d
e
Alexa IC50
dofetilide IC50
b
c
f
compd
R
binding
11 (8)
CTX
(nM)
(μM)
patch clamp inh. at 10 μM (%)
7
12
13
14
15
16
17
18
19
H
52 (8)
15 (12)
5.4 (2)
2.6 (2)
36 (2)
3.8 (4)
3.9 (42)
1.8 (4)
3.4 (4)
>30 (2)
24 (2)
30 (2)
13 (2)
34
71
methyl
6.9 (12)
9.0 (2)
5.7 (2)
10 (2)
3-pyridyl
4-pyridyl
5-pyrimidinyl
2-pyrazinyl
2-pyrimidinyl
2-thiazolyl
2-oxazolyl
6.0 (4)
5.2 (42)
6.0 (4)
5.6 (4)
6.5 (2)
19 (12)
67 (2)
31 (2)
>30 (2)
>30 (2)
>30 (2)
>30 (2)
70
35
85
72
a
b
Numbers in parentheses represent numbers of determinations. Standard deviations were less than 30% of the measured value. Antagonism of
c
d
e
MCP-1 binding to hCCR2. Antagonism of chemotaxis activity. Alexa whole blood activity (see ref 10 for assay protocol). Dofetilide hERG
binding activity. Inhibition of hERG potassium current at 10 μM from single determination of patch clamp assay.
f
a
Table 3. Modification on the Right-Hand Side Moiety
a
See the Table 2 footnotes.
enough to meet our criteria, especially in chemotaxis. However,
moving one of the 5-pyrimidinyl nitrogen atoms one-atom
closer to the 2-pyridyl ring provided the 2-pyrazinyl analogue
16, which was potent in CCR2 binding affinity (IC50 = 6 nM)
and chemotaxis activity (IC50 = 3.8 nM). Equally important, 16
was very potent in a human whole blood assay (Alexa assay),10
with an IC50 of 6.5 nM. Unfortunately, 16 exhibited 70%
inhibition of the hERG potassium current at 10 μM in the
915
dx.doi.org/10.1021/ml200199c|ACS Med. Chem. Lett. 2011, 2, 913−918

ACS Medicinal Chemistry Letters
Letter
patch clamp assay despite its weak activity in the dofetilide
assay (IC50 > 30 μM). Moving the nitrogen atom at the 4-
position of the pyrazinyl one-atom closer to the 2-pyridyl
provided the 2-pyrimidinyl analogue 17. This analogue is as
potent as 16 in CCR2 binding affinity (IC50 = 5.2 nM) and
chemotaxis activity (IC50 = 3.9 nM) but about 3-fold weaker
than 16 in the whole blood assay (IC50 = 19 nM). In contrast
to 16, 17 exhibited weak hERG activity in the patch clamp
assay, with 35% inhibition of the potassium current. The two
five-membered heteroaryl analogues 18 (2-thiazolyl) and 19 (2-
oxazolyl) were potent in the CCR2 binding and chemotaxis
assays, although they were slightly less active than 17 in the
whole blood assay. Despite their weak hERG activity in the
dofetilide assay, they were potent in the patch clamp assay
(72−85% inhibition at 10 μM).
3), we considered replacing the three-atom linker between the
middle carbonyl and the trifluoromethylphenyl in 17 with a
carbocycle. Because piperidine possesses a length of about three
atoms counting from the 1-position to the 4-position, it was
chosen for our exploration (Table 3). Thus, replacement of the
three-atom linker in 17 with a piperidine afforded compound
20. Strikingly, 20 is as potent as 17 in the CCR2 binding and
chemotaxis assays and is only 2-fold less active than 17 in the
whole blood assay. Unfortunately, this replacement led to an
enhancement in hERG binding activity as reflected by an IC50
of 9 μM in the dofetilide assay. To modulate the hERG activity,
we sought to adjust the polarity of the 3-trifluoromethylphenyl
in 20 by replacing it with trifluoromethylpyridyl to provide 6-
trifluoromethyl-2-pyridyl analogue 21 and 4-trifluoromethyl-2-
pyridyl analogue 22. With the pyridyl nitrogen sterically
shielded by both the piperidine ring and the trifluoromethyl,
21 showed no improvement in hERG activity. With the pyridyl
nitrogen at the 4-position of the trifluoromethyl that is more
solvent exposed, 22 exhibited weaker hERG activity (IC50 = 28
μM) in the dofetilide assay than 20 but is still not weak enough
to meet our criteria. Of special note on 22 is its potent
chemotaxis and whole blood activity, with an IC50 of 1.9 nM in
the chemotaxis assay and an IC50 of 12 nM in the whole blood
assay. Replacement of 4-trifluoromethyl-2-pyridyl in 22 with 4-
trifluoromethyl-2-pyrimidinyl to further increase polarity did
not improve the hERG activity (23, IC50 = 26 μM), while
replacement of 4-trifluoromethylpyridyl in 22 with 6-trifluor-
omethyl-4-pyrimidinyl (24) reduced the hERG activity to an
IC50 of >30 μM but resulted in a 3-fold loss in CCR2 binding
affinity. The hERG binding activity of 22 can also be reduced
by replacing the trifluoromethyl in 22 with cyano (25) or by
introducing a hydroxyl group at the 4-position of the piperidine
(26), but both compounds exhibited 10−12 times weaker
chemotaxis activity than 22.
Having identified 4-hydroxy-4-[5-(pyrimidin-2-yl)pyridin-2-
yl]cyclohexyl as the preferred left-hand side moiety, we
extended our SAR studies to the right-hand side moiety of
17. On the basis of the extended conformation of the right-
hand side moiety of 17 from its X-ray crystal structure (Figure
Given its superior profile, 17 was further evaluated in vitro
and in vivo. In addition to being a potent human CCR2
antagonist (Table 2), 17 is also a potent murine CCR2
antagonist, exhibiting IC50 values of 17 and 13 nM in mouse
Figure 3. X-ray crystal structure of two molecules of compound 17.
Gray, carbon atoms; white, hydrogen atoms; blue, nitrogen atoms; red,
oxygen atoms; and green, fluorine atoms.
a
Scheme 1. Synthesis of 17
a
Reagent and conditions: (a) n-BuLi, toluene, −78 °C to room temperature, 79%. (b) iPrMgCl, THF, nickel(II) acetylacetonate, 1,2-
bis(diphenylphosphino)ethane. (c) 4 N HCl, THF, H2O, 58% for two steps. (d) Benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate, DMF, Et3N, 96%. (e) 4 N HCl in dioxane, MeOH, 100%. (f) NaBH(OAc)3, iBuOH, 66%.
916
dx.doi.org/10.1021/ml200199c|ACS Med. Chem. Lett. 2011, 2, 913−918

ACS Medicinal Chemistry Letters
Letter
and rat binding assays and 16 and 2.8 nM in mouse and rat
chemotaxis assays. In signaling assays, 17 is potent in inhibiting
CCR2 mediated signaling events such as intracellular calcium
mobilization and ERK (extracellular signal-regulated kinase)
phosphorylation with IC50 values of 3.3 and 0.5 nM,
respectively. Cerep screens revealed that 17 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, chemokine receptors including CCR1,
CCR3, CCR5, CXCR3, and CXCR5, and additional GPCRs. In
hERG patch clamp assay, 17 inhibited hERG potassium current
with an IC50 of 20 μM.
In vitro ADME (absorption, distribution, metabolism, and
excretion) profiling revealed that 17 has a moderate
permeability across Caco-2 monolayers with a value of 3.1 ×
10−6 cm/s. In protein binding, 17 had a free fraction of 23% in
human serum. When incubated with human liver microsomes,
17 exhibited a moderate intrinsic clearance, with a half-life
(t1/2) of 89 min. When 17 was incubated with human S9 with
or without NADPH and the cofactor glutathione, no
glutathione adducts were detected. Compound 17 is not a
cytochrome P450 (CYP) inhibitor, with IC50 values of >30 μM
against five major CYP isozymes CYP1A2, CYP2C9,
CYP2C19, CYP2D6, and CYP3A4. Compound 17 is not a
CYP inducer at concentrations up to 30 μM.
The pharmacokinetics of 17 was assessed in rats and dogs
(Table 4). Following iv administration of 17, the total systemic
clearance was moderate in rats but low in dogs. 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.
As a result, 17 exhibited a moderate half-life in both species
after iv administration (2.5 and 2.4 h). When administered
orally, 17 was absorbed rapidly, with peak concentration time
(Tmax) at 1.2 h for rats and 0.25 h for dogs. A similar half-life
was observed in both species between iv dosing and po dosing.
Compound 17 was well absorbed, with an oral bioavailability of
78% in both species.
product 31. The ketal in 31 was converted to a ketone (32) by
treatment with 4 N HCl in THF. Reductive amination of 32
with 33, which was generated by coupling of 34 with 35
followed by removal of the Boc group, gave rise to a mixture of
two isomers with a ratio of about 2:1 that was separated by
silica gel chromatography. The major isomer was the active
isomer 17, while the minor isomer was inactive at a
concentration of 1 μM in the CCR2 binding assay. The
stereochemistry at the cyclohexyl in 17 was illustrated by X-ray
crystallography (Figure 3), with the hydroxyl trans to the
amino. In the crystal structure, the cyclohexyl assumes a chair
conformation with 5-(2-pyrimidinyl)-2-pyridinyl at the equato-
rial position and the amino and hydroxyl at the axial positions.
In summary, we discovered a new series of CCR2 antagonists
by reversing the connections of the left-hand side moiety and
the right-hand side moiety to the 3-aminopyrrolidine core
structure in the INCB3284 series. In contrast to the INCB3284
series in which an R configuration on pyrrolidine is critical to
binding to CCR2, an S configuration on pyrrolidine in the new
series is superior to an R configuration. SAR studies at the 4-
position of cyclohexyl on the left-hand side led to the
identification of a potent CCR2 antagonist 17 (INCB8761/
PF-4136309) with high selectivity, weak hERG activity, high
free fraction in protein binding, and an excellent in vitro and in
vivo ADMET (ADME and toxicology) profile. INCB8761/PF-
4136309 has entered human clinical trials.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures for the synthesis of compound 17 and
characterization data for compounds 1−26. 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.
Table 4. Pharmacokinetic Parameters of 17
ACKNOWLEDGMENTS
a
a
■
rats
dogs
We thank Lynn Leffet, Karen Gallagher, Patricia Feldman,
Bitao Zhao, Yanlong Li, and Robert Collins for technical
assistance.
iv
dose (mg/kg)
CL (L/h/kg)
Vss (L/kg)
t1/2 (h)
2
2
1.41
7.0
0.46
0.62
2.4
REFERENCES
2.5
■
po
(1) Kinne, R. W.; Brauer, R.; Stuhlmuller, B.; Palombo-Kinne, E.;
Burmester, G. Macrophages in rheumatoid arthritis. Arthritis Res. 2000,
2, 189−202.
dose (mg/kg)
Cmax (nM)
Tmax (h)
10
610
1.2
10
20039
0.25
(2) Feria, M.; Diaz-Conzalez, F. The CCR2 receptor as a therapeutic
target. Expert Opin. Ther. Pat. 2006, 16, 49−57.
AUC (nM h)
t1/2 (h)
2723
2.5
35560
3.2
(3) Xia, M.; Sui, Z. Recent development in CCR2 antagonists. Expert
Opin. Ther. Pat. 2009, 19, 295−303.
F %
78
78
(4) Pease, J. E.; Horuk, R. Chemokine receptor antagonists: Part I.
Expert Opin. Ther. Pat. 2009, 19, 39−58.
a
Three animals per study.
(5) Struthers, M.; Pasternak, A. CCR2 antagonists. Curr. Top. Med.
Chem. 2010, 10, 1278−1298.
The synthesis of this series of compounds is exemplified by
(6) Pasternak, A.; Goble, S. D.; Struthers, M.; Vicario, P. P.; Ayala, J.
M.; Di Salvo, J.; Kilburn, R.; Wisniewski, T.; DeMartino, J. A.; Mills, S.
G.; Yang, L. Discovery of a potent and orally bioavailable CCR2 and
CCR5 dual antagonist. ACS Med. Chem. Lett. 2010, 1, 14−18.
(7) Cherney, R. J.; Mo, R.; Meyer, D. T.; Voss, M. E.; Yang, M. G.;
Santella, J. B. III; Duncia, J. V.; Lo, Y. C.; Yang, G.; Miller, P. B.;
Scherle, P. A.; Zhao, Q.; Mandlekar, S.; Cvijic, M. E.; Barrish, J. C.;
Decicco, C. P.; Carter, P. H. γ-Lactams as glycinamide replacements in
compound 17 as illustrated in Scheme 1. Selective lithiation at
the 2-bromine of 2,5-dibromopyridine 27 with n-butyl lithium
in toluene followed by addition of 1,4-cyclohexanedione
monoethylene ketal 28 produced the adduct 29. Treatment
of 29 with isopropylmagnesium chloride followed by addition
of nickel(II) acetylacetonate, 1,2-bis(diphenylphosphino)-
ethane, and 2-iodopyrimidine (30) provided the coupling
917
dx.doi.org/10.1021/ml200199c|ACS Med. Chem. Lett. 2011, 2, 913−918

ACS Medicinal Chemistry Letters
Letter
cyclohexane-based CC chemokine receptor 2 (CCR2) antagonists.
Bioorg. Med. Chem. Lett. 2010, 20, 2425−2430.
(8) Peace, S.; Philp, J.; Brooks, C.; Piercy, V.; Moores, K.; Smethurst,
C.; Watson, S.; Gaines, S.; Zippoli, M.; Mookherjee, C.; Ife, R.
Identification of a sulfonamide series of CCR2 antagonists. Bioorg.
Med. Chem. Lett. 2010, 20, 3961−3964.
(9) Xue, C.-B.; Wang, A.; Meloni, D.; Zhang, K.; Kong, L.; Feng, H.;
Glenn, J.; Huang, T.; Zhang, Y.; Cao, G.; Anand, R.; Zheng, C.; Xia,
M.; Han, Q.; Robinson, D. J.; Storace, L.; Shao, L.; Li, M.; Brodmerkel,
C. M.; Covington, M.; Scherle, P.; Diamond, S.; Yeleswaram, S; Vaddi,
K.; Newton, R.; Hollis, G.; Friedman, S.; Metcalf, B. Discovery of
INCB3344, a potent, selective and orally bioavailable antagonist of
human and murine CCR2. Bioorg. Med. Chem. Lett. 2010, 20, 7473−
7478.
(10) Zheng, C.; Cao, G.; Xia, M.; Feng, H.; Glenn, J.; Anand, R.;
Zhang, K.; Huang, T.; Wang, A.; Kong, L.; Li, M.; Galya, L.; Hughes,
R. O.; Devraj, R.; Morton, P. A.; Rogier, D. J.; Covington, M.;
Baribaud, F.; Shin, N.; Scherle, P.; Diamond, S.; Yeleswaram, S.; Vaddi,
K.; Newton, R.; Hollis, G.; Friedman, S.; Metcalf, B.; Xue, C.-B.
Discovery of INCB10820/PF-4178903, a potent, selective and orally
bioavailable dual CCR2 and CCR5 antagonist. Bioorg. Med. Chem. Lett.
2011, 21, 1442−1446.
(11) Xue, C.-B.; Feng, H.; Cao, G.; Huang, T.; Glenn, J.; Anand, R.;
Meloni, D.; Zhang, K.; Kong, L.; Wang, A.; Zhang, Y.; Zheng, C.; Xia,
M.; Chen, L.; Tanaka, H.; Han, Q.; Robinson, D. J.; Modi, D.; Storace,
L.; Shao, L.; Sharief, V.; Li, M.; Covington, M.; Scherle, P.; Diamond,
S.; Emm, T.; Yeleswaram, S.; Contel, N.; Vaddi, K.; Newton, R.;
Hollis, G.; Friedman, S.; Metcalf, B. Discovery of INCB3284, a potent,
selective and orally bioavailable hCCR2 antagonist. ACS Med. Chem.
Lett. 2011, 2, 450−454.
(12) Finlayson, K.; Pennington, A. J.; Kelly, J. S. [3H]dofetilide
binding in SHSY5Y and HEK 293 cells expressing a hERG-like K+
channel? Eur. J. Pharmacol. 2001, 412, 203−212.
918
dx.doi.org/10.1021/ml200199c|ACS Med. Chem. Lett. 2011, 2, 913−918