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

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.

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.

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