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.
Percy H Carter  1 ,  Gregory D Brown  1 ,  Robert J Cherney  1 ,  Douglas G Batt  1 ,  Jing Chen  1 ,  Cheryl M Clark  1 ,  Mary Ellen Cvijic  1 ,  John V Duncia  1 ,  Soo S Ko  1 ,  Sandhya Mandlekar  1 ,  Ruowei Mo  1 ,  David J Nelson  1 ,  Jian Pang  1 ,  Anne V Rose  1 ,  Joseph B Santella 3rd  1 ,  Andrew J Tebben  1 ,  Sarah C Traeger  1 ,  Songmei Xu  1 ,  Qihong Zhao  1 ,  Joel C Barrish  1
Affiliations
  • 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.
PMID: 25893046 DOI: 10.1021/ml500505q
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.