Identification and characterization of INCB9471, an allosteric noncompetitive small-molecule antagonist of C-C chemokine receptor 5 with potent inhibitory activity against monocyte migration and HIV-1 infection

Journal of Pharmacology and Experimental Therapeutics

Volumn 338, Issue 1, 2011, Pages 228-239

  Shin, Niu ^a   Solomon, Kim ^a   Zhou, Naiming ^a   Wang, Kathy He ^a   Garlapati, Vasudha ^a   Thomas, Beth ^a   Li, Yanlong ^a   Covington, Maryanne ^a   Baribaud, Frederic ^a   Erickson Viitanen, Susan ^a   Czerniak, Phil ^a   Contel, Nancy ^a   Liu, Phillip ^a   Burn, Timothy ^a   Hollis, Gregory ^a   Yeleswaram, Swamy ^a   Vaddi, Kris ^a   Xue, Chu Biao ^a   Metcalf, Brian ^a   Friedman, Steve ^a   Scherle, Peggy ^a   Newton, Robert ^a   more..

^a Experimental Station   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 [[4 [4 [2 ETHOXY 5 (TRIFLUOROMETHYL) 2,3 DIHYDRO 1H INDEN1 YL] 3 METHYLPIPERAZIN 1 YL] 4 METHYLPIPERIDIN 1 YL]CARBONYL] 4,6 DIMETHYLPYRIMIDINE DIHYDROCHLORIDE; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; APLAVIROC; CALCIUM ION; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; INCB 9471; MARAVIROC; UNCLASSIFIED DRUG; VICRIVIROC;

ANIMAL CELL; ARTICLE; CALCIUM MOBILIZATION; CELL MIGRATION; CONTROLLED STUDY; DRUG BINDING SITE; DRUG IDENTIFICATION; DRUG POTENCY; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; MONOCYTE; NONHUMAN; PRIORITY JOURNAL; RECEPTOR BLOCKING; SITE DIRECTED MUTAGENESIS;

ALLOSTERIC SITE; ANIMALS; ANTI-HIV AGENTS; CELL MOVEMENT; CELLS, CULTURED; DOSE-RESPONSE RELATIONSHIP, DRUG; HEK293 CELLS; HIV INFECTIONS; HIV-1; HUMANS; MACACA FASCICULARIS; MONOCYTES; PIPERAZINES; PROTEIN BINDING; PYRIMIDINES; RECEPTORS, CCR5;

EID: 79959508604     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.111.179531     Document Type: Article

References (37)

1. Abdi R, Smith RN, Makhlouf L, Najafian N, Luster AD, Auchincloss H Jr., and Sayegh MH (2002) The role of CC chemokine receptor 5 (CCR5) in islet allograft rejection. Diabetes 51:2489-2495. (Pubitemid 34827398)
2. Bajetto A, Bonavia R, Barbero S, and Schettini G (2002) Characterization of chemokines and their receptors in the central nervous system: physiopathological implications. J Neurochem 82:1311-1329.
3. Baroudy BM, Clasder JW, Josien HB, McCombie SW, McKittrick BA, Miller MW, Neustadt BR, Palani A, Smith EM, Steensma R, et al. (2000), inventors; Schering-Plough Corp., assignee. Piperazine derivatives useful as CCR5 antagonists. World patent WO200006558. 2000 Sep 11.
4. Belnoue E, Kayibanda M, Deschemin JC, Viguier M, Mack M, Kuziel WA, and Rénia L (2003) CCR5 deficiency decreases susceptibility to experimental cerebral malaria. Blood 101:4253-4259. (Pubitemid 36857785)
5. Castonguay LA, Weng Y, Adolfsen W, Di Salvo J, Kilburn R, Caldwell CG, Daugherty BL, Finke PE, Hale JJ, Lynch CL, et al. (2003) 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 42:1544-1550. (Pubitemid 36205961)
6. Cohen C, DeJesus E, Mills A, Pierone G., Kumar P, Ruane P, Elion R, Fusco G, Levy R, Solomon K, et al. (2007) Potent antiretroviral activity of the once daily antagonist INCB009471 over 14 days of monotherapy, at the Fourth IAS Conference on HIV Pathogenesis, Treatment, and Prevention; 2007 July 22-25; Sydney, Australia. International AIDs Society, Geneva, Switzerland.
7. Combadiere C, Ahuja SK, Tiffany HL, and Murphy PM (1996) Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1α, MIP-1β, and RANTES. J Leukoc Biol 60:147-152. (Pubitemid 26248894)
8. Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E, et al. (1996) Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multiple Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273:1856-1862.
9. Doms RW (2001) Chemokine receptors and HIV entry. AIDS 15 (Suppl 1):S34-S35.
10. Dragic T, Trkola A, Thompson DA, Cormier EG, Kajumo FA, Maxwell E, Lin SW, Ying W, Smith SO, Sakmar TP, et al. (2000) A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc Natl Acad Sci USA 97:5639-5644. (Pubitemid 30313771)
11. Ehlert FJ (1988) Estimation of the affinities of allosteric ligands using radioligand binding and pharmacological null methods. Mol Pharmacol 33:187-194.
12. Fahmy NM, Yamani MH, Starling RC, Ratliff NB, Young JB, McCarthy PM, Feng J, Novick AC, and Fairchild RL (2003) Chemokine and chemokine receptor gene expression indicates acute rejection of human cardiac transplants. Transplantation 75:72-78. (Pubitemid 36139698)
13. Gao W, Faia KL, Csizmadia V, Smiley ST, Soler D, King JA, Danoff TM, and Hancock WW (2001) Beneficial effects of targeting CCR5 in allograft recipients. Transplantation 72:1199-1205. (Pubitemid 33026595)
14. Garcia-Perez J, Rueda P, Staropoli I, Kellenberger E, Alcami J, Arenzana-Seisdedos F, and Lagane B (2011) New insights into the mechanisms whereby low molecular weight CCR5 ligands inhibit HIV-1 infection. J Biol Chem 286:4978-4990.
15. Gonzalez E, Dhanda R, Bamshad M, Mummidi S, Geevarghese R, Catano G, Anderson SA, Walter EA, Stephan KT, Hammer MF, et al. (2001) Global survey of genetic variation in CCR5, RANTES, and MIP-1α: impact on the epidemiology of the HIV-1 pandemic. Proc Natl Acad Sci USA 98:5199-5204. (Pubitemid 32397106)
16. Houle M, Thivierge M, Le Gouill C, Stankovà J, and Rola-Pleszczynski M (1999) IL-10 up-regulates CCR5 gene expression in human monocytes. Inflammation 23:241-251. (Pubitemid 29301567)
17. Huffnagle GB, McNeil LK, McDonald RA, Murphy JW, Toews GB, Maeda N, and Kuziel WA (1999) Cutting edge: Role of C-C chemokine receptor 5 in organ-specific and innate immunity to Cryptococcus neoformans. J Immunol 163:4642-4646. (Pubitemid 29501222)
18. Kazmierski WM, Boone L, Lawrence W, Watson C, and Kenakin T (2002) CCR5 chemokine receptors: gatekeepers of HIV-1 infection. Curr Drug Targets Infect Disord 2:265-278.
19. Kenakin T (2004) G-protein coupled receptors as allosteric machines. Receptors Channels 10:51-60.
20. Kuhmann SE, Pugach P, Kunstman KJ, Taylor J, Stanfield RL, Snyder A, Strizki JM, Riley J, Baroudy BM, Wilson IA, et al. (2004) Genetic and phenotypic analyses of human immunodeficiency virus type 1 escape from a small-molecule CCR inhibitor. J Virol 78:2790-2807. (Pubitemid 38314338)
21. Lee B, Sharron M, Montaner LJ, Weissman D, and Doms RW (1999) Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dentritic cells, and differentially conditioned monocyte-derived macrophages. Proc Natl Acad Sci USA 96:5215-5220. (Pubitemid 29214563)
22. Mitsuya H, Maeda K, Shibayama S, and Takaoka Y (2002), inventors; Ono Pharmaceutical Co., Ltd., assignee. Drugs containing triazaspiro [5.5] undecane derivatives as the active ingredient. World patent WO2002074769. 2002 Sept 26.
23. Onuffer JJ and Horuk R (2002) Chemokines, chemokine receptors and small-molecule antagonists: recent developments. Trends Pharm Sci 23:459-467. (Pubitemid 35279607)
24. Perros M, Rice D, David A, Stammen B, Luzia C, and Wood A (2001), inventors; Pfizer Limited, assignee. Tryasolyl tropane derivatives as CCR5 modulators. World patent WO2001090106. 2001 Nov 29.
25. Poignard P, Saphire EO, Parren PW, and Burton DR (2001) gp120: Biologic aspects of structural features. Annu Rev Immunol 19:253-274. (Pubitemid 32368036)
26. Segerer S, Cui Y, Eitner F, Goodpaster T, Hudkins KL, Mack M, Cartron JP, Colin Y, Schlondorff D, and Alpers CE (2001) Expression of chemokines and chemokine receptors during human renal transplant rejection. Am J Kidney Dis 37:518-531. (Pubitemid 32195291)
27. Seibert C, Ying W, Gavrilov S, Tsamis F, Kuhmann SE, Palani A, Tagat JR, Clader JW, McCombie SW, Baroudy BM, et al. (2006) Interaction of small molecule inhibitors of HIV-1 entry with CCR5. Virology 349:41-54.
28. Trkola A, Kuhmann SE, Strizki JM, Maxwell E, Ketas T, Morgan T, Pugach P, Xu S, Wojcik L, Tagat J, et al. (2002) HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use. Proc Natl Acad Sci USA 99:395-400. (Pubitemid 34060372)
29. Tsamis F, Gavrilov S, Kajumo F, Seibert C, Kuhmann S, Ketas T, Trkola A, Palani A, Clader JW, Tagat JR, et al. (2003) 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 77:5201-5208. (Pubitemid 36460934)
30. Watson C, Jenkinson S, Kazmierski W, and Kenakin T (2005) The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor. Mol Pharmacol 67:1268-1282. (Pubitemid 40410427)
31. Wong MM and Fish EN (2003) Chemokines: attractive mediators of the immune response. Semin Immunol 15:5-14. (Pubitemid 36092174)
32. Wu L, Gerard NP, Wyatt R, Choe H, Parolin C, Ruffing N, Borsetti A, Cardoso AA, Desjardin E, Newman W, et al. (1996) CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 384:179-183. (Pubitemid 26386475)
33. Xue C, Cao G, Huang T, Chen L, Zhang K, Wang A, Meloni D, Anand R, Glenn J, and Metcalf BW (2005), inventors; Incyte Corp., assignee. Piperazinylpiperidine derivatives as chemokine receptor antagonists. World patent WO2005101838. 2005 Oct 27.
34. Xue C, Chen L, Cao G, Zhang K, Wang A, Meloni D, Glenn J, Anand R, Xia M, Kong L, et al. (2010) Discovery of INCB9471, a potent, selective, and orally bioavailable CCR5 antagonist with potent anti-HIV-1 activity. ACS Med Chem Lett 1:483-487.
35. Yang YF, Mukai T, Gao P, Yamaguchi N, Ono S, Iwaki H, Obika S, Imanishi T, Tsujimura T, Hamaoka T, et al. (2002) A non-peptide CCR5 antagonist inhibits collagen-induced arthritis by modulating T cell migration without affecting anticollagen T cell responses. Eur J Immunol 32:2124-2132. (Pubitemid 34965875)
36. Zapico I, Coto E, Rodríguez A, Alvarez C, Torre JC, and Alvarez V (2000) CCR5 (chemokine receptor-5) DNA-polymorphism influences the severity of rheumatoid arthritis. Genes Immun 1:288-289.
37. Zhang YJ and Moore JP (1999) Will multiple coreceptors need to be targeted by inhibitors of human immunodeficiency virus type 1 entry? J Virol 73:3443-3448.