Interaction of small molecule inhibitors of HIV-1 entry with CCR5

Virology

Volumn 349, Issue 1, 2006, Pages 41-54

  Seibert, Christoph ^a   Ying, Weiwen ^b   Gavrilov, Svetlana ^c   Tsamis, Fotini ^c   Kuhmann, Shawn E ^d   Palani, Anandan ^e   Tagat, Jayaram R ^e   Clader, John W ^e   McCombie, Stuart W ^e   Baroudy, Bahige M ^e   Smith, Steven O ^b   Dragic, Tatjana ^c   Moore, John P ^d   Sakmar, Thomas P ^a  

^a ROCKEFELLER UNIVERSITY   (United States)

^b STONY BROOK UNIVERSITY   (United States)

^c ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^d WEILL CORNELL MEDICAL COLLEGE   (United States)

^e MERCK RESEARCH LABORATORIES   (United States)

Author keywords

AD101; CCR5; CCR5 inhibitors; GPCR; HIV 1; SCH C; TAK 779

Indexed keywords

1 [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4 METHYL 4 [3 METHYL 4 [1 [4 (TRIFLUOROMETHYL)PHENYL]ETHYL] 1 PIPERAZINYL]PIPERIDINE; 4 [(4 BROMOPHENYL)(ETHOXYIMINO)METHYL] 1' [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4' METHYL 1,4' BIPIPERIDINE; 4 [1 [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4 METHYL 4 PIPERIDINYL] 2 METHYL 1 [1 [4 (TRIFLUOOROMETHYL)PHENYL]ETHYL]PIPERAZINE; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; N [4 [[[6,7 DIHYDRO 2 (4 METHYLPHENYL) 5H BENZOCYCLOHEPTEN 8 YL]CARBONYL]AMINO]BENZYL] N,N DIMETHYL 2H TETRAHYDROPYRAN 4 AMINIUM CHLORIDE; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; ARTICLE; CONTROLLED STUDY; DRUG MECHANISM; DRUG STRUCTURE; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; HYDROPHOBICITY; NONHUMAN; PREDICTION; PRIORITY JOURNAL; PROTEIN FUNCTION; SEQUENCE HOMOLOGY; STRUCTURE ACTIVITY RELATION; VIRUS INFECTIVITY;

AMIDES; BINDING SITES; CELL LINE; CYCLIC N-OXIDES; HIV FUSION INHIBITORS; HIV-1; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; MUTAGENESIS, SITE-DIRECTED; PIPERIDINES; PROTEIN STRUCTURE, SECONDARY; PYRIDINES; QUATERNARY AMMONIUM COMPOUNDS; RECEPTORS, CCR5;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 33646514864     PISSN: 00426822     EISSN: 10960341     Source Type: Journal    
DOI: 10.1016/j.virol.2006.01.018     Document Type: Article

References (80)

1. Baba M., Nishimura O., Kanzaki N., Okamoto M., Sawada H., Iizawa Y., Shiraishi M., Aramaki Y., Okonogi K., Ogawa Y., Meguro K., and Fujino M. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci. U.S.A. 96 10 (1999) 5698-5703
2. Berger E.A., Murphy P.M., and Farber J.M. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu. Rev. Immunol. 17 (1999) 657-700
3. Billick E., Seibert C., Pugach P., Ketas T., Trkola A., Endres M.J., Murgolo N.J., Coates E., Reyes G.R., Baroudy B.M., Sakmar T.P., Moore J.P., and Kuhmann S.E. A single amino acid explains the differential sensitivity of human and rhesus macaque CCR5 to small molecule inhibitors of human immunodeficiency virus type 1 entry and suggests a mechanism of action for these inhibitors. J. Virol. 78 8 (2004) 4134-4144
4. Blanpain C., Doranz B.J., Vakili J., Rucker J., Govaerts C., Baik S.S., Lorthioir O., Migeotte I., Libert F., Baleux F., Vassart G., Doms R.W., and Parmentier M. Multiple charged and aromatic residues in CCR5 amino-terminal domain are involved in high affinity binding of both chemokines and HIV-1 Env protein. J. Biol. Chem. 274 49 (1999) 34719-34727
5. Blanpain C., Doranz B.J., Bondue A., Govaerts C., De Leener A., Vassart G., Doms R.W., Proudfoot A., and Parmentier M. The core domain of chemokines binds CCR5 extracellular domains while their amino terminus interacts with the transmembrane helix bundle. J. Biol. Chem. 278 7 (2003) 5179-5187
6. Brunger A.T. X-PLOR, version 3.1. A system for X-ray Crystallography and NMR (1992), Yale Univ. Press, New Haven, CT
7. Burley S.K., and Petsko G.A. Weakly polar interactions in proteins. Adv. Protein Chem. 39 (1988) 125-189
8. Carter P.H. Chemokine receptor antagonism as an approach to anti-inflammatory therapy: 'just right' or plain wrong?. Curr. Opin. Chem. Biol. 6 4 (2002) 510-525
9. Castonguay L.A., Weng Y., Adolfsen W., Di Salvo J., Kilburn R., Caldwell C.G., Daugherty B.L., Finke P.E., Hale J.J., Lynch C.L., Mills S.G., MacCoss M., Springer M.S., and DeMartino J.A. Binding of 2-Aryl-4-(piperidin-1-yl)butanamines and 1,3,4-trisubstituted pyrrolidines to human CCR5: a molecular modeling-guided mutagenesis study of the binding pocket. Biochemistry 42 6 (2003) 1544-1550
10. Cormier E.G., and Dragic T. The crown and stem of the V3 loop play distinct roles in human immunodeficiency virus type 1 envelope glycoprotein interactions with the CCR5 coreceptor. J. Virol. 76 17 (2002) 8953-8957
11. De Clercq E. New developments in anti-HIV chemotherapy. Biochim. Biophys. Acta 1587 2-3 (2002) 258-275
12. Dean M., Carrington M., Winkler C., Huttley G.A., Smith M.W., Allikmets R., Goedert J.J., Buchbinder S.P., Vittinghoff E., Gomperts E., Donfield S., Vlahov D., Kaslow R., Saah A., Rinaldo C., Detels R., and O'Brien S.J. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia growth and development study, multicenter AIDS cohort study, multicenter hemophilia cohort study, San Francisco City Cohort, ALIVE Study. Science 273 5283 (1996) 1856-1862
13. Doranz B.J., Lu Z.H., Rucker J., Zhang T.Y., Sharron M., Cen Y.H., Wang Z.X., Guo H.H., Du J.G., Accavitti M.A., Doms R.W., and Peiper S.C. Two distinct CCR5 domains can mediate coreceptor usage by human immunodeficiency virus type 1. J. Virol. 71 9 (1997) 6305-6314
14. Douek D.C., Picker L.J., and Koup R.A. T cell dynamics in hiv-1 infection. Annu. Rev. Immunol. 21 (2003) 265-304
15. Dragic T. An overview of the determinants of CCR5 and CXCR4 co-receptor function. J. Gen. Virol. 82 Pt. 8 (2001) 1807-1814
16. Dragic T., Trkola A., Lin S.W., Nagashima K.A., Kajumo F., Zhao L., Olson W.C., Wu L., Mackay C.R., Allaway G.P., Sakmar T.P., Moore J.P., and Maddon P.J. Amino-terminal substitutions in the CCR5 coreceptor impair gp120 binding and human immunodeficiency virus type 1 entry. J. Virol. 72 1 (1998) 279-285
17. Dragic T., Trkola A., Thompson D.A., Cormier E.G., Kajumo F.A., Maxwell E., Lin S.W., Ying W., Smith S.O., Sakmar T.P., and Moore J.P. A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc. Natl. Acad. Sci. U.S.A. 97 10 (2000) 5639-5644
18. Eilers M., Patel A.B., Liu W., and Smith S.O. Comparison of helix interactions in membrane and soluble alpha-bundle proteins. Biophys. J. 82 5 (2002) 2720-2736
19. Farzan M., Choe H., Martin K.A., Sun Y., Sidelko M., Mackay C.R., Gerard N.P., Sodroski J., and Gerard C. HIV-1 entry and macrophage inflammatory protein-1beta-mediated signaling are independent functions of the chemokine receptor CCR5. J. Biol. Chem. 272 11 (1997) 6854-6857
20. Farzan M., Choe H., Vaca L., Martin K., Sun Y., Desjardins E., Ruffing N., Wu L., Wyatt R., Gerard N., Gerard C., and Sodroski J. A tyrosine-rich region in the N terminus of CCR5 is important for human immunodeficiency virus type 1 entry and mediates an association between gp120 and CCR5. J. Virol. 72 2 (1998) 1160-1164
21. Farzan M., Mirzabekov T., Kolchinsky P., Wyatt R., Cayabyab M., Gerard N.P., Gerard C., Sodroski J., and Choe H. Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. Cell 96 5 (1999) 667-676
22. Forbes I.T., Cooper D.G., Dodds E.K., Hickey D.M., Ife R.J., Meeson M., Stockley M., Berkhout T.A., Gohil J., Groot P.H., and Moores K. CCR2B receptor antagonists: conversion of a weak HTS hit to a potent lead compound. Bioorg. Med. Chem. Lett. 10 16 (2000) 1803-1806
23. Fraser C.M., Wang C.D., Robinson D.A., Gocayne J.D., and Venter J.C. Site-directed mutagenesis of m1 muscarinic acetylcholine receptors: conserved aspartic acids play important roles in receptor function. Mol. Pharmacol. 36 6 (1989) 840-847
24. Gerlach L.O., Skerlj R.T., Bridger G.J., and Schwartz T.W. Molecular interactions of cyclam and bicyclam non-peptide antagonists with the CXCR4 chemokine receptor. J. Biol. Chem. 276 17 (2001) 14153-14160
25. Hartley O., Klasse P.J., Sattentau Q.J., and Moore J.P. V3: HIV's switch-hitter. AIDS Res. Hum. Retrovir. 21 2 (2005) 171-189
26. Hatse S., Princen K., Gerlach L.O., Bridger G., Henson G., De Clercq E., Schwartz T.W., and Schols D. Mutation of Asp(171) and Asp(262) of the chemokine receptor CXCR4 impairs its coreceptor function for human immunodeficiency virus-1 entry and abrogates the antagonistic activity of AMD3100. Mol. Pharmacol. 60 1 (2001) 164-173
27. Hesselgesser J., Ng H.P., Liang M., Zheng W., May K., Bauman J.G., Monahan S., Islam I., Wei G.P., Ghannam A., Taub D.D., Rosser M., Snider R.M., Morrissey M.M., Perez H.D., and Horuk R. Identification and characterization of small molecule functional antagonists of the CCR1 chemokine receptor. J. Biol. Chem. 273 25 (1998) 15687-15692
28. Horuk R. Development and evaluation of pharmacological agents targeting chemokine receptors. Methods 29 4 (2003) 369-375
29. Howard O.M., Shirakawa A.K., Turpin J.A., Maynard A., Tobin G.J., Carrington M., Oppenheim J.J., and Dean M. Naturally occurring CCR5 extracellular and transmembrane domain variants affect HIV-1 co-receptor and ligand binding function. J. Biol. Chem. 274 23 (1999) 16228-16234
30. Javadpour M.M., Eilers M., Groesbeek M., and Smith S.O. Helix packing in polytopic membrane proteins: role of glycine in transmembrane helix association. Biophys. J. 77 3 (1999) 1609-1618
31. Kazmierski W., Bifulco N., Yang H., Boone L., DeAnda F., Watson C., and Kenakin T. Recent progress in discovery of small-molecule CCR5 chemokine receptor ligands as HIV-1 inhibitors. Bioorg. Med. Chem. 11 (2003) 2663-2676
32. Kenakin T. G-protein coupled receptors as allosteric machines. Recept. Channels 10 2 (2004) 51-60
33. Kenakin T. New concepts in drug discovery: collateral efficacy and permissive antagonism. Nat. Rev., Drug Discov. 4 (2005) 919-927
34. LaBranche C.C., Galasso G., Moore J.P., Bolognesi D.P., Hirsch M.S., and Hammer S.M. HIV fusion and its inhibition. Antiviral. Res. 50 2 (2001) 95-115
35. Labrosse B., Brelot A., Heveker N., Sol N., Schols D., De Clercq E., and Alizon M. Determinants for sensitivity of human immunodeficiency virus coreceptor CXCR4 to the bicyclam AMD3100. J. Virol. 72 8 (1998) 6381-6388
36. Liang M., Mallari C., Rosser M., Ng H.P., May K., Monahan S., Bauman J.G., Islam I., Ghannam A., Buckman B., Shaw K., Wei G.P., Xu W., Zhao Z., Ho E., Shen J., Oanh H., Subramanyam B., Vergona R., Taub D., Dunning L., Harvey S., Snider R.M., Hesselgesser J., Morrissey M.M., and Perez H.D. Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J. Biol. Chem. 275 25 (2000) 19000-19008
37. Liu R., Paxton W.A., Choe S., Ceradini D., Martin S.R., Horuk R., MacDonald M.E., Stuhlmann H., Koup R.A., and Landau N.R. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86 3 (1996) 367-377
38. Maeda K., Nakata H., Koh Y., Miyakawa T., Ogata H., Takaoka Y., Shibayama S., Sagawa K., Fukushima D., Moravek J., Koyanagi Y., and Mitsuya H. Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. J. Virol. 78 16 (2004) 8654-8662
39. Maeda K., Nakata H., Ogata H., Koh Y., Miyakawa T., and Mitsuya H. The current status of, and challenges in, the development of CCR5 inhibitors as therapeutics for HIV-1 infection. Curr. Opin. Pharmacol. 4 5 (2004) 447-452
40. Michael N.L., and Moore J.P. HIV-1 entry inhibitors: evading the issue. Nat. Med. 5 7 (1999) 740-742
41. Mirzadegan T., Diehl F., Ebi B., Bhakta S., Polsky I., McCarley D., Mulkins M., Weatherhead G.S., Lapierre J.M., Dankwardt J., Morgans D., Wilhelm R., and Jarnagin K. Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists: binding to a common chemokine receptor motif within the helical bundle. J. Biol. Chem. 275 33 (2000) 25562-25571
42. Moore J.P., and Stevenson M. New targets for inhibitors of HIV-1 replication. Nat. Rev., Mol. Cell Biol. 1 1 (2000) 40-49
43. Naya A., Kobayashi K., Ishikawa M., Ohwaki K., Saeki T., Noguchi K., and Ohtake N. Discovery of a novel CCR3 selective antagonist. Bioorg. Med. Chem. Lett. 11 9 (2001) 1219-1223
44. Naya A., Sagara Y., Ohwaki K., Saeki T., Ichikawa D., Iwasawa Y., Noguchi K., and Ohtake N. Design, synthesis, and discovery of a novel CCR1 antagonist. J. Med. Chem. 44 9 (2001) 1429-1435
45. O'Brien S.J., and Moore J.P. The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS. Immunol. Rev. 177 (2000) 99-111
46. O'Hara B.M., and Olson W.C. HIV entry inhibitors in clinical development. Curr. Opin. Pharmacol. 2 5 (2002) 523-528
47. Palani A., Shapiro S., Clader J.W., Greenlee W.J., Cox K., Strizki J., Endres M., and Baroudy B.M. Discovery of 4-[(Z)-(4-Bromophenyl)-(ethoxyimino)methyl]-1(-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4(-methyl-1,4(-bipiperidine N-Oxide (SCH 351125): an orally bioavailable human CCR5 antagonist for the treatment of HIV infection. J. Med. Chem. 44 21 (2001) 3339-3342
48. Palani A., Shapiro S., Josien H., Bara T., Clader J.W., Greenlee W.J., Cox K., Strizki J.M., and Baroudy B.M. Synthesis, SAR, and biological evaluation of oximino-piperidino-piperidine amides: 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity. J. Med. Chem. 45 14 (2002) 3143-3160
49. Palani A., Shapiro S., Clader J.W., Greenlee W.J., Blythin D., Cox K., Wagner N.E., Strizki J., Baroudy B.M., and Dan N. Biological evaluation and interconversion studies of rotamers of SCH 351125, an orally bioavailable CCR5 antagonist. Bioorg. Med. Chem. Lett. 13 4 (2003) 705-708
50. Palani A., Shapiro S., Clader J.W., Greenlee W.J., Vice S., McCombie S., Cox K., Strizki J., and Baroudy B.M. Oximino-piperidino-piperidine-based CCR5 antagonists: Part 2. Synthesis, SAR and biological evaluation of symmetrical heteroaryl carboxamides. Bioorg. Med. Chem. Lett. 13 4 (2003) 709-712
51. Palczewski K., Kumasaka T., Hori T., Behnke C.A., Motoshima H., Fox B.A., Le Trong I., Teller D.C., Okada T., Stenkamp R.E., Yamamoto M., and Miyano M. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289 5480 (2000) 739-745
52. Paterlini M.G. Structure modeling of the chemokine receptor CCR5: implications for ligand binding and selectivity. Biophys. J. 83 6 (2002) 3012-3031
53. Perrin D.D., Dempsey B., and Serjeant E.P. pKa Prediction for Organic Acids and Bases (1981), Chapman and Hall, London
54. Princen K., Hatse S., Vermeire K., Aquaro S., De Clercq E., Gerlach L.O., Rosenkilde M., Schwartz T.W., Skerlj R., Bridger G., and Schols D. Inhibition of human immunodeficiency virus replication by a dual CCR5/CXCR4 antagonist. J. Virol. 78 23 (2004) 12996-13006
55. Rabut G.E., Konner J.A., Kajumo F., Moore J.P., and Dragic T. Alanine substitutions of polar and nonpolar residues in the amino-terminal domain of CCR5 differently impair entry of macrophage- and dualtropic isolates of human immunodeficiency virus type 1. J. Virol. 72 4 (1998) 3464-3468
56. Reynes J., Rouzier R., Kanouni T., Baillat V., Baroudy B., Keung A., Markowitz M., and Laughlin M. SCH-C: safety and antiviral effects of a CCR5 receptor antagonist in HIV-1 infected subjects. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA (2002)
57. Rosenkilde M.M., Gerlach L.O., Jacobsen J.S., Skerlj R.T., Bridger G.J., and Schwartz T.W. Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor-transfer of binding site to the CXCR3 receptor. J. Biol. Chem. 279 4 (2003) 3033-3041
58. Ross T.M., Bieniasz P.D., and Cullen B.R. Multiple residues contribute to the inability of murine CCR-5 to function as a coreceptor for macrophage-tropic human immunodeficiency virus type 1 isolates. J. Virol. 72 3 (1998) 1918-1924
59. Rucker J., Samson M., Doranz B.J., Libert F., Berson J.F., Yi Y., Smyth R.J., Collman R.G., Broder C.C., Vassart G., Doms R.W., and Parmentier M. Regions in beta-chemokine receptors CCR5 and CCR2b that determine HIV-1 cofactor specificity. Cell 87 3 (1996) 437-446
60. Samson M., Libert F., Doranz B.J., Rucker J., Liesnard C., Farber C.M., Saragosti S., Lapoumeroulie C., Cognaux J., Forceille C., Muyldermans G., Verhofstede C., Burtonboy G., Georges M., Imai T., Rana S., Yi Y., Smyth R.J., Collman R.G., Doms R.W., Vassart G., and Parmentier M. Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382 6593 (1996) 722-725
61. Schurmann D., Rouzier R., Nougarede R., Reynes J., Falkenheuer G., Raffi F., Michelet C., Tarral A., Hoffmann C., Kiunke J., Sprenger H., vanLier J., Sansone A., Jackson M., and Laughlin M. SCH-D: antiviral activity of a CCR5 receptor antagonist. 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA (2004)
62. Schwarz M.K., and Wells T.N.C. New therapeutics that modulate chemokine networks. Nat. Rev., Drug Discov. 1 (2002) 347-358
63. Seibert C., and Sakmar T.P. Small-molecule antagonists of CCR5 and CXCR4: a promising new class of anti-HIV-1 drugs. Curr. Pharm. Des. 10 17 (2004) 2041-2062
64. Seibert C., Cadene M., Sanfiz A., Chait B.T., and Sakmar T.P. Tyrosine sulfation of CCR5 N-terminal peptide by tyrosylprotein sulfotransferases 1 and 2 follows a discrete pattern and temporal sequence. Proc. Natl. Acad. Sci. U.S.A. 99 17 (2002) 11031-11036
65. Shieh T., Han M., Sakmar T.P., and Smith S.O. The steric trigger in rhodopsin activation. J. Mol. Biol. 269 3 (1997) 373-384
66. Shiraishi M., Aramaki Y., Seto M., Imoto H., Nishikawa Y., Kanzaki N., Okamoto M., Sawada H., Nishimura O., Baba M., and Fujino M. Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety. J. Med. Chem. 43 10 (2000) 2049-2063
67. Strader C.D., Fong T.M., Tota M.R., Underwood D., and Dixon R.A. Structure and function of G protein-coupled receptors. Annu. Rev. Biochem. 63 (1994) 101-132
68. Strader C.D., Fong T.M., Graziano M.P., and Tota M.R. The family of G-protein-coupled receptors. FASEB J. 9 9 (1995) 745-754
69. Strizki J.M., Xu S., Wagner N.E., Wojcik L., Liu J., Hou Y., Endres M., Palani A., Shapiro S., Clader J.W., Greenlee W.J., Tagat J.R., McCombie S., Cox K., Fawzi A.B., Chou C.C., Pugliese-Sivo C., Davies L., Moreno M.E., Ho D.D., Trkola A., Stoddart C.A., Moore J.P., Reyes G.R., and Baroudy B.M. SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 98 22 (2001) 12718-12723
70. Tagat J.R., McCombie S.W., Steensma R.W., Lin S., Nazareno D.V., Baroudy B., Vantuno N., Xu S., and Liu J. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. I: 2(S)-methyl piperazine as a key pharmacophore element. Bioorg. Med. Chem. Lett. 11 16 (2001) 2143-2146
71. Tagat J.R., Steensma R.W., McCombie S.W., Nazareno D.V., Lin S.I., Neustadt B.R., Cox K., Xu S., Wojcik L., Murray M.G., Vantuno N., Baroudy B.M., and Strizki J.M. Piperazine-based CCR5 antagonists as HIV-1 inhibitors: II. Discovery of 1-[(2,4-Dimethyl-3-pyridinyl)carbonyl]-4-methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoro-methyl)phenyl]ethyl]-1-piperazinyl]- piperidine N1-Oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist. J. Med. Chem. 44 21 (2001) 3343-3346
72. 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., and 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-piperaz inyl]-4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist. J. Med. Chem. 47 10 (2004) 2405-2408
73. Ting P.C., Lee J.F., Wu J., Umland S.P., Aslanian R., Cao J., Dong Y., Garlisi C.G., Gilbert E.J., Huang Y., Jakway J., Kelly J., Liu Z., McCombie S., Shah H., Tian F., Wan Y., and Shih N.Y. The synthesis of substituted bipiperidine amide compounds as CCR3 antagonists. Bioorg. Med. Chem. Lett. 15 5 (2005) 1375-1378
74. Trent J.O., Wang Z.X., Murray J.L., Shao W., Tamamura H., Fujii N., and Peiper S.C. Lipid bilayer simulations of CXCR4 with inverse agonists and weak partial agonists. J. Biol. Chem. 278 47 (2003) 47136-47144
75. Tsamis F., Gavrilov S., Kajumo F., Seibert C., Kuhmann S., Ketas T., Trkola A., Palani A., Clader J.W., Tagat J.R., McCombie S., Baroudy B., Moore J.P., Sakmar T.P., and Dragic T. Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry. J. Virol. 77 9 (2003) 5201-5208
76. Watson C., Jenkinson S., Kazmierski W., and Kenakin T.P. The CCR5 receptor-based mechanism of action of 873140, a potent allosteric non-competitive HIV entry-inhibitor. Mol. Pharmacol. 67 4 (2005) 1268-1282
77. Wu L., Paxton W.A., Kassam N., Ruffing N., Rottman J.B., Sullivan N., Choe H., Sodroski J., Newman W., Koup R.A., and Mackay C.R. CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro. J. Exp. Med. 185 9 (1997) 1681-1691
78. Yang Y.F., Mukai T., Gao P., Yamaguchi N., Ono S., Iwaki H., Obika S., Imanishi T., Tsujimura T., Hamaoka T., and Fujiwara H. A non-peptide CCR5 antagonist inhibits collagen-induced arthritis by modulating T cell migration without affecting anti-collagen T cell responses. Eur. J. Immunol. 32 8 (2002) 2124-2132
79. Zhang Y.J., and Moore J.P. Will multiple coreceptors need to be targeted by inhibitors of human immunodeficiency virus type 1 entry?. J. Virol. 73 4 (1999) 3443-3448
80. Zhang Y., Lou B., Lal R.B., Gettie A., Marx P.A., and Moore J.P. Use of inhibitors to evaluate coreceptor usage by simian and simian/human immunodeficiency viruses and human immunodeficiency virus type 2 in primary cells. J. Virol. 74 15 (2000) 6893-6910