title: Discovery of a 4-Azetidinyl-1-thiazoyl-cyclohexane CCR2 Antagonist as a Development Candidate.
abstract: We have discovered a novel series of 4-azetidinyl-1-aryl-cyclohexanes as CCR2 antagonists. Divergent SAR studies on hCCR2 and hERG activities led to the discovery of compound 8d, which displayed good hCCR2 binding affinity (IC50, 37 nM) and potent functional antagonism (chemotaxis IC50, 30 nM). It presented an IC50 of >50 μM in inhibition of the hERG channel and had no effect on the QTc interval up to 10 mg/kg (i.v.) in anesthetized guinea pig and dog CV studies. It also displayed high selectivity over other chemokine receptors and GPCRs, and amendable oral bioavailability in dogs and primates. In a thioglycollate-induced inflammation model in hCCR2KI mice, it had ED50 of 3 mg/kg on inhibition of the influx of leukocytes, monocytes/macrophages, and T-lymphocytes.
authors.affiliation: Janssen Research and Development, LLC , Welsh & McKean Roads, Box 776, Spring House, Pennsylvania 19477, United States.
authors.forename: Xuqing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Janssen Research and Development, LLC , Welsh & McKean Roads, Box 776, Spring House, Pennsylvania 19477, United States.
authors.forename: Cuifen
authors.initials: C
authors.lastname: Hou
authors.affiliation: Janssen Research and Development, LLC , Welsh & McKean Roads, Box 776, Spring House, Pennsylvania 19477, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Hufnagel
authors.affiliation: Janssen Research and Development, LLC , Welsh & McKean Roads, Box 776, Spring House, Pennsylvania 19477, United States.
authors.forename: Monica
authors.initials: M
authors.lastname: Singer
authors.affiliation: Janssen Research and Development, LLC , Welsh & McKean Roads, Box 776, Spring House, Pennsylvania 19477, United States.
authors.forename: Evan
authors.initials: E
authors.lastname: Opas
authors.affiliation: Janssen Research and Development, LLC , Welsh & McKean Roads, Box 776, Spring House, Pennsylvania 19477, United States.
authors.forename: Sandra
authors.initials: S
authors.lastname: McKenney
authors.affiliation: Janssen Research and Development, LLC , Welsh & McKean Roads, Box 776, Spring House, Pennsylvania 19477, United States.
authors.forename: Dana
authors.initials: D
authors.lastname: Johnson
authors.affiliation: Janssen Research and Development, LLC , Welsh & McKean Roads, Box 776, Spring House, Pennsylvania 19477, United States.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Sui
keywords: Azetidine; CCR2; cardiovascular (CV) safety; hERG