Alkylsulfone-containing trisubstituted cyclohexanes as potent and bioavailable chemokine receptor 2 (CCR2) antagonists

Robert J Cherney; Ruowei Mo; Michael G Yang; Zili Xiao; Qihong Zhao; Sandhya Mandlekar; Mary Ellen Cvijic; Israel F Charo; Joel C Barrish; Carl P Decicco; Percy H Carter

doi:10.1016/j.bmcl.2014.02.013

Alkylsulfone-containing trisubstituted cyclohexanes as potent and bioavailable chemokine receptor 2 (CCR2) antagonists

Bioorg Med Chem Lett. 2014 Apr 1;24(7):1843-5. doi: 10.1016/j.bmcl.2014.02.013. Epub 2014 Feb 21.

Authors

Affiliations

¹ Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States. Electronic address: [email protected].
² Research and Development, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, United States.
³ Gladstone Institute of Cardiovascular Disease, J David Gladstone Research Institutes, San Francisco, CA 94158, United States.

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.

Keywords: CCR2; CCR2 antagonist; Chemokine antagonist; GPCR.

MeSH terms

Animals
Cyclohexanes
Dose-Response Relationship, Drug
Humans
Mice
Molecular Conformation
Receptors, CCR2 / antagonists & inhibitors*
Structure-Activity Relationship
Sulfones / chemistry*

Substances

CCR2 protein, human
Cyclohexanes
Receptors, CCR2
Sulfones

Grants and funding

R01 HL102475/HL/NHLBI NIH HHS/United States