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

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 ?-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.

SUBMITTER: Carter PH

PROVIDER: S-EPMC4394346 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Carter Percy H PH Brown Gregory D GD Cherney Robert J RJ Batt Douglas G DG Chen Jing J Clark Cheryl M CM Cvijic Mary Ellen ME Duncia John V JV Ko Soo S SS Mandlekar Sandhya S Mo Ruowei R Nelson David J DJ Pang Jian J Rose Anne V AV Santella Joseph B JB Tebben Andrew J AJ Traeger Sarah C SC Xu Songmei S Zhao Qihong Q Barrish Joel C JC

ACS medicinal chemistry letters 20150304 4

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. ...[more]

PMID: 25893046

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