Discovery of INCB9471, a potent, selective, and orally bioavailable CCR5 antagonist with potent anti-HIV-1 activity

Article abstract of DOI:10.1021/ml1001536

To identify a CCR5 antagonist as an HIV-1 entry inhibitor, we designed a novel series of indane derivatives based on conformational considerations. Modification on the indane ring led to the discovery of compound 22a (INCB9471) that exhibited high affinit

Full text of DOI:10.1021/ml1001536

pubs.acs.org/acsmedchemlett
Discovery of INCB9471, a Potent, Selective, and Orally
Bioavailable CCR5 Antagonist with Potent Anti-HIV-1 Activity
Chu-Biao Xue,* Lihua Chen, Ganfeng Cao, Ke Zhang, Anlai Wang, David Meloni,
Joseph Glenn, Rajan Anand, Michael Xia, Ling Kong, Taisheng Huang, Hao Feng,
Changsheng Zheng, Mei Li, Laurine Galya, Jiacheng Zhou, Niu Shin, Fredric Baribaud,
Kim Solomon, Peggy Scherle, Bitao Zhao, Sharon Diamond, Tom Emm, Douglas Keller,
Nancy Contel, Swamy Yeleswaram, Kris Vaddi, Gregory Hollis, Robert Newton,
Steven Friedman, and Brian Metcalf
Incyte Corporation, Experimental Station E336, Wilmington, Delaware 19880
ABSTRACT To identify a CCR5 antagonist as an HIV-1 entry inhibitor, we designed
a novel series of indane derivatives based on conformational considerations. Modi-
fication on the indane ring led to the discovery of compound 22a (INCB9471) that
exhibited high affinity for CCR5, potent anti-HIV-1 activity, high receptor selec-
tivity, excellent oral bioavailability, and a tolerated safety profile. INCB9471 has
entered human clinical trials.
KEYWORDS CCR5, antagonist, coreceptor, HIV-1, antiviral
CR5 is a chemokine receptor, a member of the super
family of seven-transmembrane G-protein-coupled
receptors (GPCRs), and its natural ligands include
the reverse transcriptase and protease inhibitors as it pro-
tects cells from irreversible damage by the virus. As a result,
extensive searches for small molecule CCR5 inhibitors have
been pursued, and in 2000, the first small molecule to inhibit
HIV-1 growth by binding to CCR5-TAK779-was published
in the scientific literature.7 Since then, a number of structu-
rally diverse CCR5 antagonists with potent anti-HIV-1 activ-
ity have been reported, and several compounds have
entered human clinical trials.8 In 2007, the first CCR5
antagonist maraviroc (Selzentry)9,10 was approved by the
FDA and launched by Pfizer, demonstrating the validity of
the target. Development of new CCR5 antagonists has
continued to be pursued for antiviral utility and also for
potential application in a variety of autoimmune diseases.11
The latter has been demonstrated by a primate model study
in which a small molecule CCR5 antagonist exhibited effi-
cacy in collagen-induced joint inflammation.12
We were interested in small molecule CCR5 antagonists as
HIV-1 entry inhibitors and as potential therapeutics for
autoimmune diseases. Our goal was to identify a lead
compound for optimization based on literature lead com-
pounds through rational design, with special interest in the
Schering-Plough's CCR5 antagonists as this series of com-
pounds exhibited potent antiviral activity and good pharma-
cokinetic properties.13,14 Because the phenyl ring on the
left-hand side of Schering-Plough's CCR5 antagonist Sch-D13
(I in Figure 1) is one of the key pharmacophore elements for
interaction with the CCR5 receptor, we wondered whether
C
the chemokines RANTES (regulated on activation, normal
T cell expressed, and secreted), MIP-1R, and MIP-1β
(macrophage inflammatory proteins-1R and -1β).1 In addi-
tion, CCR5 is a major coreceptor for the entry of human
immunodeficiency virus type-1 (HIV-1) into host cells.2-4
HIV-1 binds to cellular membrane protein CD4 on T-cells and
macrophages through an HIV envelope protein gp120. This
binding induces a conformational change in gp120 to ex-
pose binding sites for CCR5. Binding of CCR5 to gp120
brings the viral envelope closer to the cell surface and allows
interaction between glycoprotein gp41 on the viral envelope
and a fusion domain on the host cell surface, leading to
fusion of the viral envelope with the host cell membrane and
entry of the viral core into the host cells. Genetic studies in
populations at high risk for HIV exposure revealed that
individuals homozygous for a 32-base pair deletion in
CCR5 encoding genes (Δ32 CCR5) are highly resistant to
HIV-1 infection and are without significant health problems
attributable to a lack of functioning CCR5 receptors.5 HIV-1-
infected individuals heterozygous for Δ32 CCR5 appear to
have slower disease progression to AIDS and longer survival
periods.6 These findings strongly suggest that CCR5 is an
attractive target for potential therapeutic intervention of HIV-
1 infection. Unlike reverse transcriptase and protease inhi-
bitors that block viral replication at different stages in the
viral life cycle after the HIV-1 virus has entered host cells,
CCR5 antagonists target a much earlier stage by preventing
the entry of the virus into cells. This represents a novel
mechanism of action and may offer some advantages over
Received Date: June 28, 2010
Accepted Date: August 23, 2010
Published on Web Date: August 25, 2010
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DOI: 10.1021/ml1001536 ACS Med. Chem. Lett. 2010, 1, 483–487
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Scheme 1. Synthesis of Compounds 6a and 6ba
Figure 1
the benzyl moiety on the left-hand side could be rigidified to
enhance the binding affinity and potentially improve the
physical properties. Conformational analysis revealed that a
benzene-fused bicyclic system such as an indane could
provide the desired rigidity with retained orientation of the
phenyl ring if the connection of the bicyclic system to the
piperazine nitrogen is at the benzylic position (R-position).
On the basis of these considerations, an indane ring was
chosen as the bicyclic system for our initial exploration (II in
Figure 1). To quickly test this hypothesis, we initiated the
synthesis of a 5-bromoindane derivative as 5-bromoindan-1-
one (1) is commercially available. As outlined in Scheme 1,
reduction of 1 with NaBH4 in THF converted the ketone to an
alcohol. Following treatment of alcohol 2 with thionyl chlor-
ide, the resulting chloride was displaced with (S)-4-Boc-2-
methylpiperazine to give a mixture of two diastereomers,
which were separated by flash chromatography to provide
the diastereomerically pure 3a (fast moving isomer) and 3b
(slow moving isomer). Removal of Boc group in 3a or 3b was
followed by condensation with 1-Boc-4-piperidinone in the
presence of Ti(OiPr)4 and subsequently by addition of
Et2AlCN to give rise to 4a or 4b. Displacement of the cyano
in 4a or 4b with MeMgBr yielded 5a or 5b. Removal of Boc
group in 5a or 5b followed by coupling with 4,6-dimethyl-
pyrimidine-5-carboxylic acid afforded target compounds 6a
or 6b.
Diastereomer 6a is a potent CCR5 antagonist with IC50
values of 3.9 and 1.1 nM in MIP-1β binding assay and CCR5
chemotaxis assay, respectively, similarly potent to Sch-D,
while diastereomer 6b is much less active with an IC50 of
190 nM in MIP-1β assay (Table 1). Despite its high affinity for
CCR5, 6a is a weak HIV-1 entry inhibitor with an IC50 of
334 nM against BaL strain, being 1450-fold less active than
Sch-D. The discrepancy between the CCR5 inhibitory activity
and the antiviral activity of 6a probably reflects a differential
response of the two ligands-MIP-1β and gp120-to the
conformational change caused by the binding of the small
molecule to CCR5. We reasoned that the weak antiviral
activity of 6a might be due to the bromine substituent at
the 5-position of the indane ring, as in Sch-D the correspond-
ing substituent is a trifluoromethyl group. This consideration
a Reagents and conditions: (a) NaBH4, THF, 100%. (b) SOCl2. (c) tert-
Butyl (3S)-3-methylpiperazine-1-carboxylate, DMF, NaI, Et3N, 70 °C,
19% (4a) and 18% (4b) for two steps. (d) 4 N HCl/dioxane. (e) N-Boc-
piperidin-4-one, Ti(OiPr)4, Et3N, CH2Cl2, overnight, and then Et2AlCN,
THF, 30 °C, 5 h. (f) MeMgBr, THF, overnight. (g) 4 N HCl/dioxane. (h) 4,6-
Dimethylpyrimidine-5-carboxylic acid, BOP, Et3N, DMF, room tem-
perature, 5 h.
Table 1. CCR5 and HIV-1 Activities
CCR5 IC50 (nM)
MIP-1βa CTXb
HIV-1 IC50 (nM)c
compd
ADA
0.56
BaL
Sch-D
6a
3.0
3.9
1.2
1.1
0.23
334
6b
190
13a
20a
21a
22a
5
1.2
19
11
211
4.6
6.5
3.5
3
12
0.36
0.16
a Inhibition of binding of 250 pM 125I-labeled MIP-1β to IL-10-
stimulated human monocytes. b Inhibition of migration of IL-10-stimu-
lated human monocytes in response to 30 nM MIP-1β. c Inhibition of
HIV-1 (ADA and BaL strains) infection of PHA-activated human PBMC.
Infectivity was determined by measuring viral p24 core protein in
culture supernatants.
led us to replace the bromine in 6a with a trifluoromethyl
group.
The synthesis of the trifluoromethyl counterpart of 6a is
illustrated in Scheme 2. 2-Bromo-5-(trifluoromethyl)benzonitrile
7 was converted to an alcohol 8 by sequential reductions using
DIBALand NaBH4.Treatmentof8with thionyl chloride followed
by displacement of the resulting chloride with diethyl malonate
provided the diester 9. Saponification and subsequent decar-
boxylation yielded the monocarboxylic acid 10. Ring closure by
treatment with n-butyl lithium gave the indanone 11. Reduction
of 11 with NaBH4 afforded the alcohol 12, which was processed
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DOI: 10.1021/ml1001536 ACS Med. Chem. Lett. 2010, 1, 483–487
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Scheme 2. Synthesis of Compounds 13aa
Scheme 3. Synthesis of Compounds 20a-22aa
a Reagents and conditions: (a) DIBAL, CH2Cl2, room temperature, 1 h,
50%. (b) NaBH4, THF, 0 °C, 1 h, 88%. (c) SOCl2, 1 h. (d) Ethyl malonate,
NaH, DMF, room temperature, 3 h, 64% for two steps. (e) NaOH, EtOH/
H2O, reflux, 2 h. (f) 180 °C, 1 h, 67% for two steps. (g) n-BuLi (2ꢀ), THF/
hexanes, -78 °C, 37%. (h) NaBH4, THF/MeOH, 0 °C, 30 min, 92%.
(i) Similar procedures as described in Scheme 1.
a Reagents and conditions: (a) N-Boc-piperidin-4-one, Ti(OiPr)4, Et3N,
CH2Cl2, room temperature, 20 h, and then Et2AlCN, room temperature,
20 h, 89%. (b) MeMgBr, THF, overnight, 93%. (c) Pd(OH)2/C, H2, MeOH/
AcOH, 60 psi, 18 h, 100%. (d) Toluenesulfonic acid, toluene, reflux, 3 h,
96%. (e) (S,S)-(þ)-N,N0-bis(3,5-ditert-butylsalicylidene)-1,2-cyclohexane-
diaminomanganese(III) chloride, NaClO, 4-(3-phenylpropyl)pyridine
N-oxide, NaOH, CH2Cl2/H2O, 88%, 84% ee. (f) (1) Compound 16, EtOH,
70 °C, 2 days; (2) [(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]meth-
anesulfonic acid, MeCN, 70% for two steps; (3) 1 N NaOH, 99%. (g) NaH,
RI, DMF. (h and i) Similar procedures as in Scheme 1.
to the final product 13a (less polar diastereomer) in a manner
analogous to that described in Scheme 1. As shown in Table 1,
replacement of the bromine in 6a with trifluoromethyl retained
the CCR5 potency in both MIP-1βand chemotaxis assays but, as
expected, improved the antiviral IC50 from 334 to 19 nM against
BaL virus strain. Despite the 18-fold improvement over 6a,
however, 13a is still 82-fold less active than Sch-D in the antiviral
activity. By analogy with Sch-D, we decided to introduce an
alkoxy residue at the 2-position of the indane ring.
diastereomers by MIP-1β assay (Table 1). The minor (1S,2S)-
indanyl diastereomer 19b was elaborated to provide the inactive
isomers 20b-22b, which showed IC50 values of >1000 nM in
MIP-1β assay.
Unlike the synthesis of 6a and 13a, the alkoxy analogues
of 13a were synthesized through a nonlinear sequence by
assembly of the middle piperazinyl-piperidine core (16)
prior to attachment of the indane ring to the piperazine
(Scheme 3). This approach allowed us to exploit the structure-
activity relationship at the 2-position of the indane ring more
efficiently. Intermediate 16 was prepared by reaction of
(S)-1-benzyl-2-methylpiperazine 14 with 1-Boc-4-piperidi-
none in an analogous manner as depicted in Scheme 1
and subsequent debenzylation by hydrogenolysis. A hydro-
xyl group was introduced at the 2-position of the indane ring
through regioselective ring opening with 16 of (1S,2R)-
indane epoxide 18, which was obtained with 84% ee by
dehydration of 12 followed by asymmetric epoxidation
using a Jacobson's catalyst.15 Without purification, ring
opening of the crude 18 generated a mixture of two diaster-
eomers 19a and 19b with a ratio of ∼9:1, which was
separated by flash chromatography. The absolute stereo-
chemistry of the major (1R,2R)-indanyl diastereomer 19a
was confirmed by X-ray crystallography. Alkylation at the
hydroxyl, Boc deprotection, and coupling with 4,6-dimethyl-
pyrimidine-5-carboxylic acid converted 19a to target com-
pounds 20a-22a that were determined to be the active
Substitution at the 2-position of the indane ring in 13a with
a hydroxyl group resulted in a 40-fold loss in CCR5 activity
(20a, Table 1), which was completely recovered once the
hydroxyl was methylated (21a), suggesting that a hydroxyl is
too polar to be tolerated at this position for CCR5 binding.
Disappointingly, introducing a methoxy residue to the 2-po-
sition of the indane ring was accompanied only by a minor
improvement in antiviral activity (11 nM for 21a vs 19 nM for
13a). Remarkably, replacement of the methyl group in 21a
with ethyl provided a very potent entry inhibitor 22a
(INCB9471) with subnanomolar potency in both ADA and
BaL strains and, therefore, is as potent as Sch-D. The 69-fold
enhancement in antiviral potency by a one-carbon homo-
logation in going from methyl in 21a to ethyl in 22a may be
ascribed to a better interaction of the latter molecule with the
CCR5 receptor that leads to a more profound conformational
change of the receptor required for optimally blocking
binding of gp120.
INCB9471 exists as a 1:1 mixture of two rotamers in
solution. Rotation around the amide bond between the
pyrimidinecarbonyl and the piperidine nitrogen is slow
enough to be detected by chiral high-performance liquid
chromatography and NMR. When crystallized with an acid,
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Table 2. PK Parameters of INCB9471
metabolized INCB9471 to its O-de-ethylated metabolite
(compound 20a). No glutathione adducts of INCB9471 or its
known metabolites were detected when INCB9471 was in-
cubated with human S9, with or without NADPH and the
cofactor glutathione. INCB9471 is not a CYP inhibitor, with IC50
values of >25 μM against five major CYP isozymes CYP3A4,
CYP2D6, CYP1A2, CYP2C9, and CYP2C19 nor a CYP inducer
at concentrations up to 30 μM.
In vivo, INCB9471 exhibited low systemic clearance and
high volume of distribution when administered iv in rats and
dogs, which resulted in a long half-life of 6 h in rats and 11 h in
dogs (Table 2). Longer half-lives were observed when dosed
orally in both species. The oral bioavailability was maximum
in rats (F = 100%) and near maximum in dogs (F = 95%).
The high level of plasma concentrations at 24 h (C24 h)
relative to the peak concentrations (Cmax), coupled with the
long oral half-life in both species, underscores a potential for
once a day dosing for this compound.
Given the excellent in vitro and in vivo profiles, INCB9471
was selected for preclinical evaluation. The safety profile
from GLP toxicology studies in rodents and primates justified
its advancement into human clinical trials. Phase I and phase
II human clinical trials demonstrated that INCB9471 was
safe and efficacious in viral load reduction and exhibited a
better PK profile (T1/2 = 58-60 h in repeat dosing) than Sch-
D (T1/2 = 28-33 h in repeat dosing).16
rats
dogs
1/20
dose iv/po (mg/kg)
CL (L/h/kg)
1/20
0.62
4.1
0.2
3.8
11
Vdss (L/h)
iv
T
1/2 (h)
6
AUC (nM h)
2898
7854
T
C
C
T
max (h)
max (nM)
24 h (nM)
1/2 (h)
3
0.5
14007
4071
1088
12
po
17
149779
95
AUC (nM h)
F (%)
55160
100
the di-HCl crystalline salt form predominantly exists as one
rotamer while the bistoluenesulfonic acid crystalline salt
form predominantly exists as the other rotamer. Once
dissolved in water, the predominant rotamer rapidly con-
verts to the other rotamer, resulting in an equilibrium of a 1:1
ratio within 1 h at 37 °C.
INCB9471 was further evaluated in vitro. Kinetic studies
indicated that INCB9471 rapidly associates with human
CCR5 but dissociates slowly with a Kd of 3.1 nM in human
peripheral blood mononuclear cells (PBMCs). It inhibited
CCR5-mediated signaling events such as intracellular calcium
mobilization, ERK phosphorylation, and CCR5 receptor inter-
nalization with IC50 values of 16, 3, and 1.5 nM, respectively. It is
a selective CCR5 antagonist, showing no significant inhibitory
activity when tested against a panel of >50 ion channels,
transporters, chemokine receptors, and additional GPCRs. Stud-
ies using incremental amounts of INCB9471 demonstrated
reductions in maximal ligand binding and ligand-induced
Ca2þ responses without concurrent changes in the affinity of
CCR5 ligands, indicating that INCB9471 is an allosteric non-
competitive CCR5 inhibitor. In anti-HIV-1 activity, INCB9471 is
potent against R5 HIV-1 strains representing the major clades
includingA,B,C,D,E,F,G,andJ,withageometricmeanIC90 for
all viruses tested to date of 9 nM in PBMCs, whereas it is inactive
against cells infected with X4 HIV-1 strains. More importantly,
INCB9471 is a potent inhibitor of mutant HIV-1 variants that are
resistant to other drugs including NRTIs, NNRTIs, PIs, and the
fusion inhibitor T20. The observed antiviral activity is not a
reflection of general cytotoxicity as INCB9471 did not exhibit
effects on cell viability at concentrations up to 25 μM when
tested against a variety of human primary cell lines. In the hERG
patch clamp assay, INCB9471 inhibited hERG potassium current
with an IC50 of 4.5 μM, which is 500 times above its mean
antiviral IC90 value.
In vitro ADMET profiling revealed that INCB9471 has a
high permeability across Caco-2 monolayers with a value of
16.5 ꢀ 10-6 cm/s, suggesting a potential for high oral absorp-
tion. Bidirectional transport studies across Caco-2 cells indi-
cated that this compound is not a substrate for P-gp or other
efflux transporters. In protein binding, INCB9471 has a free
fraction of 16% in human serum, resulting in a mean protein
binding adjusted IC90 of ∼60 nM in antiviral activity. When
incubated with human liver microsomes, INCB9471 exhibited
low intrinsic clearance. However, studies with recombinant
CYP isozymes showed that INCB9471 is a substrate for
CYP3A4 but not other major CYPs. Recombinant CYP3A4
SUPPORTING INFORMATION AVAILABLE Experimental
procedures for synthesis of compounds 6a,b, 13a, and 20a-22a
and assay protocols. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. Tel: 302-498-6706. Fax: 302-425-2750. E-mail: cxue@
incyte.com.
ACKNOWLEDGMENT We thank Naiming Zhou, Kathy He Wang,
Maryanne Covington, and Yanlong Li for technical assistance.
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