Discovery of a Potent and Orally Bioavailable Dual Antagonist of CC Chemokine Receptors 2 and 5

Percy H Carter; Gregory D Brown; Robert J Cherney; Douglas G Batt; Jing Chen; Cheryl M Clark; Mary Ellen Cvijic; John V Duncia; Soo S Ko; Sandhya Mandlekar; Ruowei Mo; David J Nelson; Jian Pang; Anne V Rose; Joseph B Santella 3rd; Andrew J Tebben; Sarah C Traeger; Songmei Xu; Qihong Zhao; Joel C Barrish

doi:10.1021/ml500505q

Discovery of a Potent and Orally Bioavailable Dual Antagonist of CC Chemokine Receptors 2 and 5

ACS Med Chem Lett. 2015 Mar 4;6(4):439-44. doi: 10.1021/ml500505q. eCollection 2015 Apr 9.

Authors

Percy H Carter¹, Gregory D Brown¹, Robert J Cherney¹, Douglas G Batt¹, Jing Chen¹, Cheryl M Clark¹, Mary Ellen Cvijic¹, John V Duncia¹, Soo S Ko¹, Sandhya Mandlekar¹, Ruowei Mo¹, David J Nelson¹, Jian Pang¹, Anne V Rose¹, Joseph B Santella 3rd¹, Andrew J Tebben¹, Sarah C Traeger¹, Songmei Xu¹, Qihong Zhao¹, Joel C Barrish¹

Affiliation

¹ Departments of Discovery Chemistry, Lead Discovery & Optimization, Preclinical Candidate Optimization, Molecular Discovery Technologies, and Disease Sciences & Biology, Research and Development, Bristol-Myers Squibb Company , Princeton, New Jersey 08543, United States.

Abstract

We describe the hybridization of our previously reported acyclic and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead to a new series of dual antagonists of CCR2 and CCR5. Installation of a γ-lactam as the spacer group and a quinazoline as a benzamide mimetic improved oral bioavailability markedly. These efforts led to the identification of 13d, a potent and orally bioavailable dual antagonist suitable for use in both murine and monkey models of inflammation.

Keywords: Chemokine; GPCR; dual antagonist; inflammation.