title: Alkylsulfone-containing trisubstituted cyclohexanes as potent and bioavailable chemokine receptor 2 (CCR2) antagonists.
abstract: We describe novel alkylsulfones as potent CCR2 antagonists with reduced hERG channel activity and improved pharmacokinetics over our previously described antagonists. Several of these new alkylsulfones have a profile that includes functional antagonism of CCR2, in vitro microsomal stability, and oral bioavailability. With this improved profile, we demonstrate that two of these antagonists, 2 and 12, are orally efficacious in an animal model of inflammatory recruitment.
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States. Electronic address: robert.cherney@bms.com.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cherney
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States.
authors.forename: Ruowei
authors.initials: R
authors.lastname: Mo
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Yang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States.
authors.forename: Zili
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States.
authors.forename: Qihong
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Mandlekar
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Cvijic
authors.affiliation: Gladstone Institute of Cardiovascular Disease, J David Gladstone Research Institutes, San Francisco, CA 94158, United States.
authors.forename: Israel F
authors.initials: IF
authors.lastname: Charo
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States.
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States.
authors.forename: Percy H
authors.initials: PH
authors.lastname: Carter
mesh_terms: D000818:Animals; D003510:Cyclohexanes; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry*
chemical_list: C515334:CCR2 protein, human; D003510:Cyclohexanes; D054390:Receptors, CCR2; D013450:Sulfones
keywords: CCR2; CCR2 antagonist; Chemokine antagonist; GPCR