title: Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist.
abstract: We report the identification of 13 (INCB3284) as a potent human CCR2 (hCCR2) antagonist. INCB3284 exhibited an IC50 of 3.7 nM in antagonism of monocyte chemoattractant protein-1 binding to hCCR2, an IC50 of 4.7 nM in antagonism of chemotaxis activity, an IC50 of 84 μM in inhibition of the hERG potassium current, a free fraction of 58% in protein binding, high selectivity over other chemokine receptors and G-protein-coupled receptors, and acceptable oral bioavailability in rodents and primates. In human clinical trials, INCB3284 exhibited a pharmacokinetic profile suitable for once-a-day dosing (T 1/2 = 15 h).
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Chu-Biao
authors.initials: CB
authors.lastname: Xue
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Feng
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Ganfeng
authors.initials: G
authors.lastname: Cao
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Taisheng
authors.initials: T
authors.lastname: Huang
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Glenn
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Rajan
authors.initials: R
authors.lastname: Anand
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: David
authors.initials: D
authors.lastname: Meloni
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Lingquan
authors.initials: L
authors.lastname: Kong
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Anlai
authors.initials: A
authors.lastname: Wang
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Xia
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Lihua
authors.initials: L
authors.lastname: Chen
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Han
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: D J
authors.initials: DJ
authors.lastname: Robinson
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Dilip
authors.initials: D
authors.lastname: Modi
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Lou
authors.initials: L
authors.lastname: Storace
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Lixin
authors.initials: L
authors.lastname: Shao
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Vaqar
authors.initials: V
authors.lastname: Sharief
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Laurine G
authors.initials: LG
authors.lastname: Galya
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Maryanne
authors.initials: M
authors.lastname: Covington
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Peggy
authors.initials: P
authors.lastname: Scherle
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Sharon
authors.initials: S
authors.lastname: Diamond
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Tom
authors.initials: T
authors.lastname: Emm
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Nancy
authors.initials: N
authors.lastname: Contel
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Kris
authors.initials: K
authors.lastname: Vaddi
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Newton
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Greg
authors.initials: G
authors.lastname: Hollis
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Friedman
authors.affiliation: Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Metcalf
keywords: CCR2; antagonist; chemokine; hERG; oral absorption