Novel 4,4-disubstituted piperidine-based C-C chemokine receptor-5 inhibitors with high potency against human immunodeficiency virus-1 and an improved human ether-a-go-go related gene (hERG) profile

Article abstract of DOI:10.1021/jm200279v

We recently described (J. Med. Chem. 2008, 51, 6538-6546) a novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif enabling this transition was the secondary sulfonamide substituent. Further finetuning of the substituent pattern in the sulfonamide paved the way to enhancing potency and bioavailability and minimizing hERG inhibition, resulting in discovery of clinical compound 122 (GSK163929).

Full text of DOI:10.1021/jm200279v

ARTICLE
pubs.acs.org/jmc
Novel 4,4-Disubstituted Piperidine-Based CꢀC Chemokine
Receptor-5 Inhibitors with High Potency against Human
Immunodeficiency Virus-1 and an Improved human
Ether-a-go-go Related Gene (hERG) Profile
Wieslaw M. Kazmierski,*,† Don L. Anderson,^ Christopher Aquino,|| Brian A. Chauder,|| Maosheng Duan,†
Robert Ferris,† Terrence Kenakin,‡ Cecilia S. Koble,† Dan G. Lang,^ Maggie S Mcintyre,^ Jennifer Peckham,||
Christian Watson,‡ Pat Wheelan,§ Andrew Spaltenstein,† Mary B. Wire,# Angilique Svolto,† and
Michael Youngman†
†Infectious Diseases Center for Excellence in Drug Discovery, ‡Molecular Discovery Research, §ID DMPK, Metabolic Pathways Center
for Excellence in Drug Discovery, ^Department of Biochemical and Analytical Pharmacology, and #Clinical Pharmacokinetics CPMS-
US, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27709, United States
S Supporting Information
b
ABSTRACT: We recently described (J. Med. Chem. 2008, 51, 6538ꢀ6546) a
novel class of CCR5 antagonists with strong anti-HIV potency. Herein, we detail
SAR converting leads 1 and 2 to druglike molecules. The pivotal structural motif
enabling this transition was the secondary sulfonamide substituent. Further fine-
tuning of the substituent pattern in the sulfonamide paved the way to enhancing
potency and bioavailability and minimizing hERG inhibition, resulting in
discovery of clinical compound 122 (GSK163929).
’ INTRODUCTION
A known approach to decreasing hERG inhibition is to
increase the polarity, although this often results in lower mem-
brane permeability and bioavailability and is illustrative of the
challenges of multidimensional optimization.21,22
The AIDS epidemic affects millions of individuals worldwide.
Although highly active antiretroviral therapy (HAART) has
resulted in a marked decline of AIDS-related deaths in the
developed world, there is a continued need for new medicines
that support simpler dosing, lower treatment cost, and fewer side
effects. Recent efforts in the area of CCR5 antagonist discovery
resulted in several advanced clinical compounds, such as vicriv-
iroc,1 (S,E)-8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-N-(4-(((1-
propyl-1H-imidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydro-
benzo[b]azocine-5-carboxamide(TAK-652),2and one FDA-approved
drug (maraviroc).3 Recent progress has been reviewed.4ꢀ12
’ RESULTS AND DISCUSSION
Herein, we describe SAR toward the discovery of clinical
compound 122 (GSK163929). We believe that the SAR developed
could also be applicable to other compound series.
Linker Modifications. Our previous work demonstrated
preference for a two- over three-carbon linker in this series.13,23
Analogues 3 and 4 (exo, data not shown), which feature a formal
migration of nitrogen from tropane bridgehead to the linker,
were less potent than 1 (Table 2, Figure 1). Low potency of
amide 5 can be rationalized by the now well-established structural
requirement for the basic amine moiety in CCR5 ligands.
Similarly, poor potency of 6 can be attributed to low pKa of
the bridgehead nitrogen (pKa = 6.37 for 6 vs 10.73 for 2,
calculated with ACD, version 11, software) due to the electron
withdrawing effect of neighboring ketone (Table 2).
Analogues 3 and 4 were synthesized from dioxolane 7,
Figure 1. Both isomers, endo 8 and exo 9 were separated, and
chemistry was carried out on individual isomers. Amine 10,
obtained from 4-phenyl-4-piperidinecarbonitrile 11, was reduc-
tively alkylated with both 8 and 9, yielding ligands 3 and 4.
In our previous communication we described the discovery of
potent and bioavailable endo C2-4,4-disubstituted piperidine
scaffold-based CCR5 antagonists 1 and 2.7ꢀ9,13ꢀ19,23
Our subsequent investigations revealed that 1 and 2 (Table 1)
also turned out to moderately inhibit hERG ion channels. In
addition, both compounds were active (defined as QTc > 5% at
10 mg/kg dose)20 in the in vivo guinea pig QTc prolongation
assay, used successfully in predicting the risk of human QT
prolongation.20 The latter is a marker for ventricular arrhythmias,
such as torsade de pointes (TdP), which has caused market
withdrawal of several drugs, such as cisapride, grepafloxicin, and
terfenadine. The incidence of TdP with noncardiac drugs is
0.01ꢀ0.001%, but it is significantly elevated (to 1ꢀ8% incidence)
with cardiac proarrhythmic drugs. Consequently, we launched an
effort designed to tune out hERG interaction and utilized hERG
and QTc screens to make critical compound progression decisions.
Received: December 27, 2010
Published: May 03, 2011
r
2011 American Chemical Society
3756
dx.doi.org/10.1021/jm200279v J. Med. Chem. 2011, 54, 3756–3767
|

Journal of Medicinal Chemistry
ARTICLE
Table 1
Table 2
Table 3
Table 4
Analogue 5 was synthesized from acid 13, which was derived
from 11 and amine 14.13,23 Ligand 6 was obtained by acylation of
ketone 15, followed by its bromination to 16 and final alkylation
with amine 14.
Analogues 17ꢀ19 were found to be virtually inactive in both
CCR5 binding and the antiviral assay (Table 3).
Inhibitor 24 incorporates the (3-exo)-3-[3-methyl-5-(1-
methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]octane
moiety also found in maraviroc, and we were surprised to find 24
to be essentially inactive (Table 4). A comparison with much
more potent exo-benzimidazole 25 may suggest that compounds
in our series may interact with CCR5 in a different binding mode
than maraviroc.
Benzimidazole Modifications. We probed the consequences
of replacing benzimidazole moiety in 1 with other aromatic
moieties, using ligands 17ꢀ19.
Compounds 17 and 18 were synthesized using known chemis-
try,13,23 while 19 was obtained by converting tropinone to endo amine
20, subsequent derivatization to phthaloates 21 and 22, and reductive
alkylation with aldehyde 23 (X, Y, Z, W = H) (Figure 2).
Both 24 and 25 were synthesized from aldehyde 23(X, Y, Z,
W = H) using chemistry described elsewhere.3,23ꢀ25
3757
dx.doi.org/10.1021/jm200279v |J. Med. Chem. 2011, 54, 3756–3767

Journal of Medicinal Chemistry
ARTICLE
Figure 1. Reagents and conditions: (a) DCM, 1,2-diaminobenzene, NaBH(OAc)3, molecular sieves, silica chromatography separation of exo and endo
isomers; (b) MeC(OEt)3, 100 ꢀC, quant; (c) 1 N HCl, acetone; (d) THF, (Boc)2O, TEA; (e) LiAlH4, Et2O; (f) DCM, molecular sieves, NaBH(OAc)3;
(g) toluene, DIBAL in toluene, ꢀ78 to ꢀ35 ꢀC, 2.5 h; (h) NaClO2, NaH2PO4, t-BuOH, water; (i) 14, HATU, Et3N, CH3CN; (j) 4N HCl dioxane;
(k) benzoic acid derivative, HATU, Et3N, CH3CN; (l) dichloromethane, pivaloyl chloride, triethylamine; (m) methanol, 0 ꢀC, Br2; (n) ethyl ether, TEA, 14,
benzene, 90 ꢀC, 12 h.
Figure 2. Reagents and conditions: (a) benzylamine, DCE, NaBH(OAc)3; (b) methanol, 10% Pd/C, H2, 45 psi; (c) THF/Et3N, N-carbethox-
yphthalimide, reflux; (d) ClCO2CH(Cl)CH3, 1.2 equiv, DCE, reflux; (e) MeOH, K2CO3, reflux; (f) dichloroethane, sodium triacetoxyborohydride, 23
(X, Y, Z, W = H); (g) 4 N HCl in dioxane; (h) DMF, HATU, DIEA, benzoic acid.
On the basis of these data, a conclusion was made that the
benzimidazole moiety was preferred in our series.
stitution (24, 26, 28), and aromatic ring substitutions
(29ꢀ31) were found to be deleterious to anti-HIV potency
(Table 5).
Tropane Ring Modification. We probed the apparent
preference for tropane moiety in CCR5 analogues by syn-
thesizing both the expanded ring size oxo analogue 48 and
fused 5ꢀ3 ring analogue 49 (Figure 4).23,26 Both compounds
were found to be essentially inactive (pIC50 CCR5 binding
assay 125I-[MIP-1β] of <5.50 and 5.47; HOS pIC50 of 5.05
and 6.00, respectively).
Substitutions on Benzimidazole Moiety. We examined the
influence of benzimidazole substitutions in analogues 24ꢀ34.
Tropanes 35ꢀ45 were synthesized from pivotal intermediates
46 and 47 (Figure 3) and further elaborated into inhibitors
24ꢀ34 using reductive alkylation chemistry, analogous to one
described in Figure 2.
Modifications of 2- benzimidazole moiety by truncation
(25), homologation (34), isosteric or heteroatom sub-
3758
dx.doi.org/10.1021/jm200279v |J. Med. Chem. 2011, 54, 3756–3767

Journal of Medicinal Chemistry
ARTICLE
Table 5
Table 6
3759
dx.doi.org/10.1021/jm200279v |J. Med. Chem. 2011, 54, 3756–3767

Journal of Medicinal Chemistry
ARTICLE
Table 7
Table 8
Table 9
Table 10
3760
dx.doi.org/10.1021/jm200279v |J. Med. Chem. 2011, 54, 3756–3767

Journal of Medicinal Chemistry
ARTICLE
Table 11
Table 12
Table 14
Table 13
Table 15
RAT iv Cl
RAT po DNAUC
Acid Derivatives. Compounds 51 and 52 were designed to
probe whether affinity to hERG21 could be decreased with
carboxylic acid moieties in 2 and its m-F-phenyl analogue 50.
While the latter turned out to be a moderate hERG inhibitor,
both 51 and 52 were inactive in hERG inhibition assay and
maintained similar potency to 50 in the antiviral assay. However,
we found out that 51 had poor MDCK permeability and 52 was
not bioavailable, likely because of its low absorption and/or high
rat in vivo clearance (Table 6).
Compounds 53 and 54, analogues of benzoic acid derivative 1,
were also designed to probe whether adding the carboxylate
moiety would be beneficial to optimizing both hERG and PK
(Table 7). Similar to 51 and 52, compounds 53 and 54 were
not permeable in MDCK or bioavailable in the rat PK model.
analogue
[mL/(kg min)]
[ng h/mL]
3
3
81
86
89
31
12
59
27
26.8
28.3
These compounds were, however, inactive in the hERG patch-
clamp assay. In addition, 54 caused no QTc prolongation in the
guinea pig model.
Further efforts to modulate compound polarity and absorp-
tion were attempted with tetrazole and acylsulfonamide bio-
isosteres 55 and 56. Both compounds maintained their anti-
viral potency with respect to other derivatives in this class but
3761
dx.doi.org/10.1021/jm200279v |J. Med. Chem. 2011, 54, 3756–3767

Journal of Medicinal Chemistry
ARTICLE
continued to exhibit low permeability and high cleareance in the
rat in vivo PK model (Table 8).
The synthesis of 55 was accomplished by converting ethyl
2-cyano-2-methylpropanoate to ester 57, followed by acylating
5813,23 with acid 59 (Figure 5).
Compounds 60ꢀ63 were designed as mimetics of acid 54.
These compounds had acceptable hERG properties, but perme-
ability and/or bioavailability in rat PK was still an issue for this
class, as exemplified by the tetrazolebenzoic acid derivative 60
(Table 9).
The synthesis of 62 can be accomplished by reacting 58 and
acid 66, which was obtained in several routine steps (Figure 6).
Results in this group of compounds strongly suggest that
while acids or acid bioisosteres maintain the antiviral potency
and exhibit acceptable hERG/QTc profile, these compounds
have poor membrane permeability and/or high in vivo
clearance.
Amide, sulfonamide, alcohol, and ester derivatives in 67ꢀ70
were also examined as potential hERG and PK modulators
(Table 10). The alcohol 67 and ester 68 were highly permeable
and bioavailable in rat PK. However, both compounds were also
moderately active in hERG. In addition, 68 was active (QTc =
7.2%) in the guinea pig model. On the other hand, sulfonamide
70 and to some degree amide 69 had low hERG pIC50, leading to
further efforts to optimize the sulfonamide series.
Positional Isomers of the Primary Sulfonamide Motif. A
comparison of properties associated with o-, m-, and p-sulfon-
amide isomers 71, 70, and 72 reveals that 70 has the best overall
profile, with 71 being relatively less potent and 72 found not to
be bioavailable in the rat PK model (Table 11). We further
explored the sulfonamide motif 70 by synthesizing the secondary
and tertiary sulfonamide analogues 73 and 74 (Table 12). While
the MDCK permeability was improved in secondary and tertiary
sulfonamides, 74 was also moderately potent in the hERG patch-
clamp assay, leading to discontinuation of the tertiary sulfonam-
ide motif-containing series. On the other hand, we decided to
further pursue the secondary sulfonamide motif in 73 because of
its promising properties.
Table 16. SAR of Halogen Substitution Pattern in the Un-
substituted Sulfonamide Class
Central Aromatic Ring Substitutions. We next attempted to
optimize the aromatic ring substitution pattern by synthesizing
75ꢀ80 (Table 13) and 81ꢀ105 (Table 14, Figure 7).24,25 Most
substitutions were found to be deleterious to anti-HIV potency
with the exception of several meta substituents, such as m-F (86),
m-Cl (87), and m-CH3 (89). In particular, compound 86 was
more bioavailable and had lower hERG potency (IC50= 63 μM)
compared to 1 (Table 15, Table 1). In contrast, potent methyl
derivative 89 was less bioavailable than 86, thus favoring further
use of the 3-F phenyl substitution (86) in subsequent optimiza-
tion efforts.
Sulfonamide Substitution Pattern. On the basis of 86, we
optimized the halogen substitution pattern in the sulfonamide-
substituted aromatic ring (Table 16).
Table 17. SAR for Alkylsulfonamides in the 2-Cl, 4-F Series
3762
dx.doi.org/10.1021/jm200279v |J. Med. Chem. 2011, 54, 3756–3767

Journal of Medicinal Chemistry
ARTICLE
Figure 3. Reagents and conditions: (a) H2, Pd/C, methanol; (b) 1-methyl-2-pyrrolidinone, DIEA, 70 ꢀC, 16 h; (c) RCH(OEt)3, reflux; (d) BrCN,
methanol, reflux; (e) CH3NCS, THF; (f) EDC, DMF; (g) trifluoroacetic acid, CDI, DMF, room temp; (h) C(OR)4, reflux; (i) 4 N HCl/dioxane, free-
base; (j) triphosgene, toluene, TEA, 80 ꢀC, 1 h.
Figure 4. Modified piperidine analogues 48 and 49.
Figure 5. Reagents and condtions: (a) dibutyl(oxo)stannane trimethylsilyl azide, toluene (80%); (b) NaOH (equiv), ethanol/water; (c) HATU, 58,
DIEA, DMF.
3763
dx.doi.org/10.1021/jm200279v |J. Med. Chem. 2011, 54, 3756–3767

Journal of Medicinal Chemistry
ARTICLE
Figure 6. Reagents and conditions: (a) 4-Br-aniline, nitromethane, AlCl3, reflux 30 min; (b) dimethylformamide, Pd(PPh3)4, Bu3SnCN, 120 ꢀC; (c) 1
N NaOHaq reflux, 20 min; (d) HATU, DIEA, DMF, 58.
Figure 7. Reagents and conditions: (a) ethyl cyanoacetate, NH4OAc, AcOH, benzene; (b) ArMgBr, CuI,THF, 2 h; (c) 2 M NaOH, room temp, 2 h;
(d) Cu2O/MeCN, reflux 30 min; (e) DIBAL-H, DCM, ꢀ40 ꢀC, 1 h; (f) DCE, 1-(8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole, sodium
triacetoxyborohydride; (g) 4 M HCl in dioxane, room temp, 1 h; (h) dichloromethane, benzoic acid derivative, HATU, Hunig base.
Figure 8. Reagents and condtions: (a) ClSO3H, 150 ꢀC; (b) dioxane/water, conc aq NH4OH, 0 ꢀC; (c) DMF, DIEA, HATU, 120.
Compounds 108ꢀ114 were synthesized from commercially
available mono- and dihalogen-substituted benzoic acids and con-
verted to sulfonamides as described in Figure 8. Inhibitor 112 was
highly bioavailable in the rat PK model, but its antiviral potency was
substantially lower than that of 108. On the other hand, compounds
108 and 109 were the most potent and bioavailable analogues in this
subseries. Owing to superior QTc data, the halogen motif in 108
Figure 9. Reagents and conditions: (a) HNO3, H2SO4; (b) MeOH,
was explored further with N-sulfonamide substituents (Table 17).
Ethyl derivatve 117 had borderline QTc property, while
cycloalkyl and propyl derivatives 116, 119, and 121 had low to
Pd/C, H2 or SnCl2, conc HCl; (c) (i) dichloromethane, pyridine,
TMSCl; (ii) pyridine, MsCl; (iii) 10 N NaOHaq, neutralize with 1 N
HCl aq; (d) N-Me-morpholine, cyanuric chloride, 115.
3764
dx.doi.org/10.1021/jm200279v |J. Med. Chem. 2011, 54, 3756–3767

Journal of Medicinal Chemistry
ARTICLE
Table 18. Reverse Sulfonamide SAR
moderate rat and/or dog bioavailabilities, excluding these com-
pounds from further consideration. On the other hand, trifluor-
oethyl and methyl derivatives 120 and 122 had acceptable rat
and/or dog bioavailability. Compound 122 also demonstrated
clinical molecule 122. Both compounds share significant
structural similarities. Remarkably minor, nonintuitive mod-
ifications, such as m-F substitution in the central ring and
halogen and sulfonamide substitutions in the benzylic acid,
resulted in a major differentiation of potency, PK, and hERG
inhibition between these compounds. Compound 122 was
more potent in HOS and PBL assays (pIC50 = 8.37 and 8.46)
than compound 1 (7.80 and 7.12). It also had an improved
some bioavailability in cyno PK (DNAUC = 38 ng h/mL at 10
3
mg/kg po dose) and thus had the most balanced profile of the
desired antiviral, hERG/QTc, and cross-species pharmacokinetic
properties.
Reverse Sulfonamides. While exploring additional com-
pound space, we applied the SAR learned in the forward
sulfonamide series (Tables 16 and 17) to design the reverse
sulfonamides (Table 18, Figure 9). The reverse sulfonamides
were somewhat less hydrophobic than the forward sulfonamides
and were found to be very potent in anti-HIV assays.27,28 Among
compounds examined, 125 had the most balanced PK properties
across several animal species and was found inactive in the QTc
assay. While 122 and 125 were in many respects comparable,
compound 122 was favored because of potential aniline meta-
bolite formation from reverse sulfonamide 125.
bioavailability in rat (AUC = 272 ng h/mL for 122 and 16
3
ng h/mL for 1) as well as improved hERG and QTc properties
3
(hERG pIC50 = 4.7, QTc = 1.2% for 122 and hERG pIC50
=
5.7, QTc = 9.4% for 1). On the basis of our work and reports
published in the meantime,21 we believe that the SAR con-
verting lead 1 to druglike 122 described herein may have more
general utility to other leads suffering from poor PK and hERG
properties.
Further synthetic details can be found in the Supporting
Information.
Preclinical Characterization of Compound 122. The allo-
metric scaling of plasma rat, dog, and monkey iv PK data for 122
predicted the human therapeutic dose at 900 mg/day (13 (mg/
kg)/day) q.d.29ꢀ31 Compound 122 underwent a 7-day safety
assessment in rats and dogs. No adverse effects were observed in
rats at the maximum 2000 (mg/kg)/day dose, which yielded
AUC = 77 000 ng h/mL for male and 160 000 ng h/mL for
’ ASSOCIATED CONTENT
S
Supporting Information. Synthesis details and analytical
b
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
3
3
female rats and resulted in a range of 36- to 74-fold safety cover in
rats. No adverse effects were observed in a 7-day dog safety
assessment at a 250 (mg/kg)/day dose, which yielded AUC =
34 900 ng h/mL in female dogs and 17 200 ng h/mL in male
’ AUTHOR INFORMATION
Corresponding Author
*Phone: 919-483-9462. Fax: 919-315-6053. E-mail: wieslaw.m.
kazmierski@gsk.com.
3
3
dogs and resulted in a range of 8- to 16-fold safety cover in dogs.
Combined virology, PK, and safety data supported further
progression of 122 to the clinic.
’ ABBREVIATIONS USED
’ CONCLUSIONS
hERG, human ether-a-go-go related gene; CCR5, CꢀC chemo-
kine receptor type 5; HAART, highly active antiretroviral ther-
apy; SAR, atructureꢀactivity relationship
We present extensive potency, hERG, and pharmacokinetics
SAR resulting in a conversion of the lead compound 1 into a
3765
dx.doi.org/10.1021/jm200279v |J. Med. Chem. 2011, 54, 3756–3767

Journal of Medicinal Chemistry
ARTICLE
’ REFERENCES
(16) Duan, M.; Kazmierski, W. M.; Aquino, C. J. Preparation of
Heterocyclylalkyl Substituted Cyclohexyl Compounds as CCR5 An-
tagonists. WO2004054581, 2004.
(17) Aquino, C. J.; Chong, P. Y.; Duan, M.; Kazmierski, W. M.
Preparation of Oxazine and Morpholine Derivatives as CCR5 Antago-
nists. WO2004055011, 2004.
(18) Peckham, J. P.; Aquino, C. J.; Kazmierski, W. M. Preparation of
Aminoalkylaryl Cyclopropyl Compounds as CCR5 Antagonists.
WO2004055010, 2004.
(19) Youngman, M.; Kazmierski, W. M.; Yang, H.; Aquino, C. J.
Preparation of Indane Compounds and Analogs as CCR5 Antagonists.
WO2004055012, 2004.
(20) Yao, X.; Anderson, D. L.; Ross, S. A.; Lang, D. G.; Desai, B. Z.;
Cooper, D. C.; Wheelan, P.; McIntyre, M. S.; Bergquist, M. L.; Mackenzie,
K. I.; Becherer, J. D.; Hashim, M. A. Predicting QT prolongation in
humans during early drug development using hERG inhibition and an
anaesthetized guinea-pig model. Br. J. Pharmacol. 2008, 1446–1456.
(21) (a) Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G
Medicinal chemistry of hERG optimizations: highlights and hang-ups.
J. Med. Chem. 2006, 49, 5029–5046. (b) Shamovsky, I.; Connolly, S.;
David, L.; Ivanova, S.; Nordꢀen, B.; Springthorpe, B.; Urbahns, K. J.
Overcoming undesirable hERG potency of chemokine receptor antago-
nists using baseline lipophilicity relationships. J. Med. Chem. 2008,
51, 1162–1178. (c) Cavalli, A.; Poluzzi, E.; De Ponti, F.; Recanatini,
M. Toward a pharmacophore for drugs inducing the long QT syndrome:
insights from a CoMFA study of HERG Kþ channel blockers. J. Med.
Chem. 2002, 45, 3844–3853. (d) Aronov, A. M. Common pharmaco-
phores for uncharged human ether-a-go-go-related gene (hERG) blockers.
J. Med. Chem. 2006, 49, 6917–6921.
(22) Winiwarter, S.; Bonham, N. M.; Ax, F.; Hallberg, A.; Lennernas,
H.; Karlen, A. Correlation of human jejunal permeability (in vivo) of
drugs with experimentally and theoretically derived parameters. A
multivariate data analysis approach. J. Med. Chem. 1998, 41, 4939–4949.
(23) Kazmierski, W. M.; Aquino, C.; Chauder, B. A.; Deanda, F.;
Ferris, R.; Jones-Hertzog, D. K.; Kenakin, T.; Koble, C. S.; Watson, C.;
Wheelan, P.; Yang, H.; Youngman, M. Discovery of bioavailable 4,-
4-disubstituted piperidines as potent ligands of the chemokine receptor
5 and inhibitors of the human immunodeficiency virus-1. J. Med. Chem.
2008, 51, 6538–6546.
(1) Tagat, J. R.; McCombie, S. W.; Nazareno, D.; Labroli, M. A.;
Xiao, Y.; Steensma, R. W.; Strizki, J. M.; Baroudy, B. M.; Cox, K.;
Lachowicz, J.; Varty, G.; Watkins, R. Piperazine-based CCR5 antagonists
as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-Ddimethyl-5-pyrimidinyl)-
carbonyl]- 4-[4-{2-methoxy-1(R)-4-(trifluoromethyl)phenyl}ethyl-3(S)-
methyl-1-piperazinyl]- 4-methylpiperidine (Sch -417690/ Sch- D), a
potent, highly selective, and orally bioavailable CCR5 antagonist. J. Med.
Chem. 2004, 47, 2405–2408.
(2) Seto, M.; Aikawa, K.; Miyamoto, N.; Aramaki, Y.; Kanzaki, N.;
Takashima, K.; Kuze, Y.; Iizawa, Y.; Baba, M.; Shiraishi, M. Highly potent
and orally active CCR5 antagonists as anti-HIV-1 agents: synthesis and
biological activities of 1-benzazocine derivatives containing a sulfoxide
moiety. J. Med. Chem. 2006, 49, 2037–2048.
(3) Wood, A.; Armour, D. The discovery of the CCR5 receptor
antagonist, UK-427,857, a new agent for the treatment of HIV infection
and AIDS. Prog. Med. Chem. 2005, 43, 239–271.
(4) Kazmierski, W. M.; Boone, L.; Lawrence, W.; Watson, C.;
Kenakin, T. CCR5 chemokine receptors: gatekeepers of HIV-1 infec-
tion. Curr. Drug Targets: Infect. Disord. 2002, 2, 265–278.
(5) Kazmierski, W.; Bifulco, N.; Yang, H.; Boone, L.; DeAnda, F.;
Watson, C.; Kenakin, T. Recent progress in discovery of small-molecule
CCR5 chemokine receptor ligands as HIV-1 inhibitors. Bioorg. Med.
Chem. 2003, 11, 2663–2676.
(6) Kazmierski, W.; Bifulco, N.; Yang, H.; Boone, L.; DeAnda, F.;
Watson, C.; Kenakin, T. Recent progress in discovery of small-molecule
CCR5 chemokine receptor ligands as HIV-1 inhibitors. [Erratum to
document cited in CA139:332100]. Bioorg. Med. Chem. 2003, 11, 4155.
(7) Kazmierski, W. M.; Kenakin, T. P.; Gudmundsson, K. S. Peptide,
peptidomimetic and small-molecule drug discovery targeting HIV-1
host-cell attachment and entry through gp120, gp41, CCR5 and
CXCR4. Chem. Biol. Drug Des. 2006, 67, 13–26.
(8) Kazmierski, W. M.; Peckham, J. P.; Duan, M.; Kenakin, T. P.;
Jenkinson, S.; Gudmundsson, K. S.; Piscitelli, S. C.; Feldman, P. L.
Recent progress in the discovery of new CCR5 and CXCR4 chemokine
receptor antagonists as inhibitors of HIV-1 entry. Part 2. Curr. Med.
Chem.: Anti-Infect. Agents 2005, 4, 133–152.
(9) Kazmierski, W. M.; Gudmundsson, K. S.; Piscitelli, S. C. Small
molecule CCR5 and CXCR4-based viral entry inhibitors for anti-HIV
therapy currently in development. Annu. Rep. Med. Chem. 2007, 42,
301–320.
(10) Tsibris, A. M. N.; Kuritzkes, D. R. Chemokine antagonists as
therapeutics: focus on HIV-1. Annu. Rev. Med. 2007, 58, 445–459.
(11) Palani, A.; Tagat, J. R. Discovery and development of small-
molecule chemokine coreceptor CCR5 antagonists. J. Med. Chem. 2006,
49, 2851–2857.
(12) Westby, M.; van der Ryst, E. CCR5 antagonists: host-targeted
antivirals for the treatment of HIV infection. Antiviral Chem. Chemother.
2005, 16, 339–354.
(13) Kazmierski, W.; Anderson, D. L.; Aquino, C. J.; Bifulco, N.;
Boone, L. R.; Boros, E. E.; Chauder, B. A.; Chong, P. Y.; Duan, M.; Ferris,
R. G.; Kenakin, T. P.; Koble, C. S.; Lang, D. G.; McLean, E.; McIntyre,
M. S.; Peckham, J. P.; Spaltenstein, A.; Svolto, A. C.; Thompson, J. B.;
Yang, H.; Youngman, M. K.; Wheelan, P. J. Novel, Potent and Bioavail-
able CCR5 Chemokine Receptor Small-Molecule Antagonists for HIV
Therapy: Scaffold Discovery and Addressing hERG Ion Channel Affinity
in the Process of Optimizing Potency and Bioavailability. Presented at
the 232nd National Meeting of the American Chemical Society, San
Francisco, CA, United States, Sep 10ꢀ14, 2006; MEDI-297.
(14) Kazmierski, W. M.; Aquino, C. J.; Bifulco, N.; Boros, E. E.;
Chauder, B. A.; Chong, P. Y.; Duan, M.; Deanda, F., Jr.; Koble, C. S.;
Mclean, E. W.; Peckham, J. P.; Perkins, A. C.; Thompson, J. B.;
Vanderwall, D. Preparation of Benzimidazolylazabicyclooctylethylpiper-
idines as CCR5 Antagonists for the Treatment of HIV Infection.
WO2004054974, 2004.
(24) Chauder, B.; Boros, E.; Du, K.; Kazmierski, W.; Koble, C.;
Thompson, J.; Tabet, E. Synthesis of 4-substituted piperidines via a mild
and scalable two-step Cu2O-mediated decarboxylation of cyanoesters.
Synth. Commun. 2006, 36, 279–284.
(25) Chauder, B. A.; Anderson, D.; Aquino, C. J.; Bifulco, N.; Boone,
L. R.; Boros, E. E.; Chong, P. Y.; Du, K. S.; Duan, M.; Ferris, R. G.;
Kazmierski, W. M.; Kenakin, T. P.; Koble, C. S.; Lang, D. G.; Peckham,
J. P.; Spaltenstein, A.; Thompson, J. B.; Youngman, M. K.; Wheelan, P. J.
Discovery and Design of Potent Piperidine-Based CCR5 Antagonists for
the Potential Treatment of HIV-1 Infection. Presented at the 232nd
National Meeting of the American Chemical Society, San Francisco, CA,
United States, Sep 10ꢀ14, 2006, 2006; MEDI-242.
(26) Zirkle, C. L.; Gerns, F. R.; Pavloff, A. M.; Burger, A. The
isomeric 3-oxa- and 3-thiagranatanin-7-ols and their derivatives; reduc-
tion of bicyclic amino ketones related to tropanone. J. Org. Chem. 1961,
26, 395–407.
(27) Jenkinson, S.; McCoy, D.; Kerner, S.; Ferris, R.; Lawrence, W.;
Fox, T.; Smith, C. Development of a high-throughput viral-free assay for
the measurement of CCR5-mediated HIV/cell fusion. Recept. Channels
2003, 9, 117–123.
(28) Hazen, R.; Harvey, R.; Ferris, R.; Craig., C; Yates, P.; Griffin, P.;
Miller, J.; Kaldor, I.; Ray, J.; Samano, V.; Furfine, E.; Spaltenstein, A.;
Hale, M.; Tung, R.; St. Clair, M.; Hanlon, M.; Boone, L. In vitro antiviral
activity of the novel, tyrosyl-based human immunodeficiency virus
(HIV) type 1 protease inhibitor brecanavir (GW640385) in combina-
tion with other antiretrovirals and against a panel of protease inhibitor-
resistant HIV. Antimicrob. Agents Chemother. 2007, 51, 3147–3154.
(29) Faetkenheuer, G.; Pozniak, A. L.; Johnson, M. A.; Plettenberg,
A.; Staszewski, S.; Hoepelman, A. I. M.; Saag, M. S.; Goebel, F. D.;
(15) Yang,H.;Kazmierski,W.M.;Aquino,C.J.PreparationofPyrrolidine
and Azetidine Compounds as CCR5 Antagonists. WO2004055016, 2004.
3766
dx.doi.org/10.1021/jm200279v |J. Med. Chem. 2011, 54, 3756–3767

Journal of Medicinal Chemistry
ARTICLE
Rockstroh, J. K.; Dezube, B. J.; Jenkins, T. M.; Medhurst, C.; Sullivan,
J. F.; Ridgway, C.; Abel, S.; James, I. T.; Youle, M.; van der Ryst, E.
Efficacy of short-term monotherapy with maraviroc, a new CCR5
antagonist, in patients infected with HIV-1. Nat. Med. (N.Y., NY, U.S.)
2005, 11, 1170–1172.
(30) Lalezari, J.; Thompson, M.; Kumar, P.; Piliero, P.; Davey, R.;
Patterson, K.; Shachoy-Clark, A.; Adkison, K.; Demarest, J.; Lou, Y.;
Berrey, M.; Piscitelli, P. Antiviral activity and safety of 873140, a novel
CCR5 antagonist, during short-term monotherapy in HIV-infected
adults. AIDS 2005, 19, 1443–1448.
(31) Yeni, P.; LaMarca, A.; Berger, D.; Cimoch, P.; Lazzarin, A.;
Salvato, P.; Smaill, F. M.; Teofilo, E.; Madison, S. J.; Nichols, W. G.;
Adkison, K. K.; Bonny, T.; Millard, J.; McCarty, D.; EPIC (CCR100136)
Study Team. Antiviral activity and safety of aplaviroc, a CCR5 antago-
nist, in combination with lopinavir/ritonavir in HIV-infected, therapy-
naive patients: results of the EPIC study (CCR100136). HIV Med. 2009,
10, 116–124.
3767
dx.doi.org/10.1021/jm200279v |J. Med. Chem. 2011, 54, 3756–3767