title: 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.
abstract: 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 Ca(2+) 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.
authors: Incyte Corporation, Wilmington, Delaware, USA.
authors: Niu
authors: N
authors: Shin
authors: Kim
authors: K
authors: Solomon
authors: Naiming
authors: N
authors: Zhou
authors: Kathy He
authors: KH
authors: Wang
authors: Vasudha
authors: V
authors: Garlapati
authors: Beth
authors: B
authors: Thomas
authors: Yanlong
authors: Y
authors: Li
authors: Maryanne
authors: M
authors: Covington
authors: Frederic
authors: F
authors: Baribaud
authors: Susan
authors: S
authors: Erickson-Viitanen
authors: Phil
authors: P
authors: Czerniak
authors: Nancy
authors: N
authors: Contel
authors: Phillip
authors: P
authors: Liu
authors: Timothy
authors: T
authors: Burn
authors: Gregory
authors: G
authors: Hollis
authors: Swamy
authors: S
authors: Yeleswaram
authors: Kris
authors: K
authors: Vaddi
authors: Chu-Biao
authors: CB
authors: Xue
authors: Brian
authors: B
authors: Metcalf
authors: Steve
authors: S
authors: Friedman
authors: Peggy
authors: P
authors: Scherle
authors: Robert
authors: R
authors: Newton
mesh_terms: D000495:Allosteric Site / Q000502:physiology; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D065100:CCR5 Receptor Antagonists; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008252:Macaca fascicularis; D009000:Monocytes / Q000187:drug effects* / Q000473:pathology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D011485:Protein Binding / Q000502:physiology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D019713:Receptors, CCR5 / Q000502:physiology
chemical_list: C560623:5-((4-(4-(2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazin-1-yl)-4-methylpiperidin-1-yl)carbonyl)-4,6-dimethylpyrimidine; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010879:Piperazines; D011743:Pyrimidines; D019713:Receptors, CCR5