PT  - JOURNAL ARTICLE
AU  - Niu Shin
AU  - Kim Solomon
AU  - Naiming Zhou
AU  - Kathy He Wang
AU  - Vasudha Garlapati
AU  - Beth Thomas
AU  - Yanlong Li
AU  - Maryanne Covington
AU  - Frederic Baribaud
AU  - Susan Erickson-Viitanen
AU  - Phil Czerniak
AU  - Nancy Contel
AU  - Phillip Liu
AU  - Timothy Burn
AU  - Gregory Hollis
AU  - Swamy Yeleswaram
AU  - Kris Vaddi
AU  - Chu-Biao Xue
AU  - Brian Metcalf
AU  - Steve Friedman
AU  - Peggy Scherle
AU  - Robert Newton
TI  - 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
AID  - 10.1124/jpet.111.179531
DP  - 2011 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 228--239
VI  - 338
IP  - 1
4099  - http://jpet.aspetjournals.org/content/338/1/228.short
4100  - http://jpet.aspetjournals.org/content/338/1/228.full
SO  - J Pharmacol Exp Ther2011 Jul 01; 338
AB  - C-C chemokine receptor 5 (CCR5) is a clinically proven target for inhibition of HIV-1 infection and a potential target for various inflammatory diseases. In this article, we describe 5-[(4-{(3S)-4-[(1R,2R)-2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine dihydrochloride (INCB9471), a potent and specific inhibitor of human CCR5 that has been proven to be safe and efficacious in viral load reduction in phase I and II human clinical trails. INCB9471 was identified using a primary human monocyte-based radioligand competition binding assay. It potently inhibited macrophage inflammatory protein-1β-induced monocyte migration and infection of peripheral blood mononuclear cells by a panel of R5-HIV-1 strains. The results from binding and signaling studies using incremental amounts of INCB9471 demonstrated INCB9471 as a noncompetitive CCR5 inhibitor. The CCR5 residues that are essential for interaction with INCB9471 were identified by site-specific mutagenesis studies. INCB9471 rapidly associates with but slowly dissociates from CCR5. When INCB9471 was compared with three CCR5 antagonists that had been tested in clinical trials, the potency of INCB9471 in blocking CCR5 ligand binding was similar to those of 4,6-dimethyl-5-{[4-methyl-4-((3S)-3-methyl-4-{(1R0–2-(methyloxy)-1-[4-(trifluoromethyl) phenyl]ethyl}-1-piperazingyl)-1-piperidinyl]carbonyl}pyrimidine (SCH-D; vicriviroc), 4-{[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxyl)methyl]-2, 5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenyl]oxy}benzoic acid hydrochloride (873140; aplaviroc), and 4,4-difluoro-N-((1S)-3-{(3-endo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenylpropyl)cyclohexanecarboxamide (UK427857; maraviroc). Its inhibitory activity against CCR5-mediated Ca2+ mobilization was also similar to those of SCH-D and 873140. Further analysis suggested that INCB9471 and UK427857 may have different binding sites on CCR5. The significance of two CCR5 antagonists with different binding sites is discussed in the context of potentially overcoming drug-resistant HIV-1 strains.