6546 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Kazmierski et al.
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 bioavailable 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. 232nd ACS National Meeting, San Francisco, CA, Sept.
10-14, 2006, MEDI-297.
Compound 55, tert-Butyl-4-{3-[4-(2-oxo-2,3-dihydro-1H-
benzimidazol-1-yl)piperidin-1-yl]propyl}-4-phenylpiperidine-
1-carboxylate. Obtained from 49 and 1-(4-piperidinyl)-1,3-
dihydro-2H-benzimidazol-2-one as described for 69. 1H NMR (400
MHz, CDCl3) δ 10.43 (m, 1H), 7.32-6.98 (m, 10H), 4.28 (m,
1H), 3.65 (m, 2H), 3.09 (m, 2H), 2.87-2.84 (m, 2H), 2.37 (m,
2H), 2.18 (m, 4H), 1.95 (m, 1H), 1.70 (m, 4H), 1.54 (m, 2H), 1.41
(s, 9H), 1.14-1.00 (m, 2H). MS (electrospray +) 519.27 (M +
1).
(17) 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 benzimidazolylazabicyclooctylethylpiperidines as
CCR5 antagonists for the treatment of HIV infection. Patent
WO2004054974, 2004.
References
(18) Yang, H.; Kazmierski, W. M.; Aquino, C. J. Preparation of pyrrolidine
and azetidine compounds as CCR5 antagonists. Patent WO2004055016,
2004.
(19) Duan, M.; Kazmierski, W. M.; Aquino, C. J. Preparation of hetero-
cyclylalkyl substituted cyclohexyl compounds as CCR5 antagonists.
Patent WO2004054581, 2004.
(20) Aquino, C. J.; Chong, P. Y.; Duan, M.; Kazmierski, W. M. Preparation
of oxazine and morpholine derivatives as CCR5 antagonists. Patent
WO2004055011, 2004.
(21) Peckham, J. P.; Aquino, C. J.; Kazmierski, W. M. Preparation of
aminoalkylaryl cyclopropyl compounds as CCR5 antagonists. Patent
WO2004055010, 2004.
(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-Dimethyl-5-pyrimidinyl)carbonyl]-
4-[4-{2-methoxy-1(R)-4-(trifluoromethyl)phenyl}ethyl-3(S)-methyl-1-pip-
erazinyl]-4-methylpiperidine (Sch-417690/Sch-D), a Potent, Highly Se-
lective, 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 infection. Curr.
Drug Targets: Inf. 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.
(22) Youngman, M.; Kazmierski, W. M.; Yang, H.; Aquino, C. J.
Preparation of indane compounds and analogs as CCR5 antagonists.
Patent WO2004055012, 2004.
(23) Dostert, P.; Imbert, T.; Bucher, B. ꢀ-3-Aminonortropane derivatives.
Fr. Demande Appl. No. 79 00971, 1982.
(24) Harrison, T.; Swain, C. J. Preparation of 3,3-disubstituted piperidines
for treating the conditions associated with an excess of tachykinins.
U.S. Patent 5807865, 1998.
(25) Giardina, G. A. M.; Grugni, M.; Rigolio, R.; Vassallo, M.; Erhard,
K.; Farina, C. A reliable and efficient synthesis of SR 142801. Bioorg.
Med. Chem. Lett. 1996, 6, 2307–2310.
(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.
(26) Emonds-Alt, X.; Bichon, D.; Ducoux, J. P.; Heaulme, M.; Miloux,
B.; Poncelet, M.; Proietto, V.; Van Broeck, D.; Vilain, P.; Neliat, G.;
Soubrie, P.; Le Fur, G.; Breliere, J. C. SR 142801, the first potent
non-peptide antagonist of the tachykinin NK3 receptor. Life Sci. 1994,
56, PL27–32.
(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-InfectiVe 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) Barnum, D.; Greene, J.; Smellie, A.; Sprague, P. Identification of Common
Functional Configurations Among Molecules. J. Chem. Inf. Comput. Sci.
1996, 36, 563–571.
(14) Watson, C.; Jenkinson, S.; Kazmierski, W.; Kenakin, T. The CCR5
receptor-based mechanism of action of 873140, a potent allosteric
noncompetitive HIV entry inhibitor. Mol. Pharmacol. 2005, 67, 1268–
1282.
(15) Pearlman, R. S.; Smith, K. M. Novel software tools for chemical
diversity. Persp. Drug DiscoVery Des. 1998, 9, 339–353.
(16) 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,
(27) Kim, D.; Wang, L.; Caldwell, C. G.; Chen, P.; Finke, P. E.; Oates,
B.; MacCoss, M.; Mills, S. G.; Malkowitz, L.; Gould, S. L.; DeMartino,
J. A.; Springer, M. S.; Hazuda, D.; Miller, M.; Kessler, J.; Danzeisen,
R.; Carver, G.; Carella, A.; Holmes, K.; Lineberger, J.; Schleif, W. A.;
Emini, E. A. Design, synthesis, and SAR of heterocycle-containing
antagonists of the human CCR5 receptor for the treatment of HIV-1
infection. Bioorg. Med. Chem. Lett. 2001, 11, 3103–3106.
(28) 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.
(29) 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. 232nd ACS National Meeting,
San Francisco, CA, Sept. 10-14, 2006, MEDI-242.
(30) 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. Re-
cept.Channels 2003, 9, 117–123.
(31) 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
combination with other antiretrovirals and against a panel of protease
inhibitor-resistant HIV. Antimicrob. Agents Chemother. 2007, 51,
3147–3154.
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