title: Discovery of INCB10820/PF-4178903, a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist.
abstract: We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist (3S,4S)-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine (19). After evaluation in 28-day toxicology studies, compound 19 (INCB10820/PF-4178903) was selected as a clinical candidate.
authors.affiliation: Incyte Corporation, Experimental Station E336, Wilmington, DE 19880, USA.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Zheng
authors.forename: Ganfeng
authors.initials: G
authors.lastname: Cao
authors.forename: Michael
authors.initials: M
authors.lastname: Xia
authors.forename: Hao
authors.initials: H
authors.lastname: Feng
authors.forename: Joseph
authors.initials: J
authors.lastname: Glenn
authors.forename: Rajan
authors.initials: R
authors.lastname: Anand
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Taisheng
authors.initials: T
authors.lastname: Huang
authors.forename: Anlai
authors.initials: A
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Kong
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Laurine
authors.initials: L
authors.lastname: Galya
authors.forename: Robert O
authors.initials: RO
authors.lastname: Hughes
authors.forename: Rajesh
authors.initials: R
authors.lastname: Devraj
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Morton
authors.forename: D Joseph
authors.initials: DJ
authors.lastname: Rogier
authors.forename: Maryanne
authors.initials: M
authors.lastname: Covington
authors.forename: Fred
authors.initials: F
authors.lastname: Baribaud
authors.forename: Niu
authors.initials: N
authors.lastname: Shin
authors.forename: Peggy
authors.initials: P
authors.lastname: Scherle
authors.forename: Sharon
authors.initials: S
authors.lastname: Diamond
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
authors.forename: Kris
authors.initials: K
authors.lastname: Vaddi
authors.forename: Robert
authors.initials: R
authors.lastname: Newton
authors.forename: Greg
authors.initials: G
authors.lastname: Hollis
authors.forename: Steven
authors.initials: S
authors.lastname: Friedman
authors.forename: Brian
authors.initials: B
authors.lastname: Metcalf
authors.forename: Chu-Biao
authors.initials: CB
authors.lastname: Xue
mesh_terms: D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D018938:Caco-2 Cells; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*
chemical_list: C515334:CCR2 protein, human; D065100:CCR5 Receptor Antagonists; C558669:N-(3-isopropyl-3-((4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)carbonyl)cyclopentyl)-3-methoxytetrahydro-2H-pyran-4-amine; D010879:Piperazines; D011714:Pyrans; D054390:Receptors, CCR2