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Optimization of Pharmacokinetics through Manipulation of Physicochemical Properties in a Series of HCV Inhibitors.

ABSTRACT: A novel series of HCV replication inhibitors based on a pyrido[3,2-d]pyrimidine core were optimized for pharmacokinetics (PK) in rats. Several associations between physicochemical properties and PK were identified and exploited to guide the design of compounds. In addition, a simple new metric that may aid in the prediction of bioavailability for compounds with higher polar surface area is described (3*HBD-cLogP).

SUBMITTER: Lazerwith SE

PROVIDER: S-EPMC4018142 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Optimization of Pharmacokinetics through Manipulation of Physicochemical Properties in a Series of HCV Inhibitors.

Lazerwith Scott E SE Bahador Gina G Canales Eda E Cheng Guofeng G Chong Lee L Clarke Michael O MO Doerffler Edward E Eisenberg Eugene J EJ Hayes Jaclyn J Lu Bing B Liu Qi Q Matles Mike M Mertzman Michael M Mitchell Michael L ML Morganelli Philip P Murray Bernard P BP Robinson Margaret M Strickley Robert G RG Tessler Megan M Tirunagari Neeraj N Wang Jianhong J Wang Yujin Y Zhang Jennifer R JR Zheng Xubin X Zhong Weidong W Watkins William J WJ

ACS medicinal chemistry letters 20110808 10

A novel series of HCV replication inhibitors based on a pyrido[3,2-d]pyrimidine core were optimized for pharmacokinetics (PK) in rats. Several associations between physicochemical properties and PK were identified and exploited to guide the design of compounds. In addition, a simple new metric that may aid in the prediction of bioavailability for compounds with higher polar surface area is described (3*HBD-cLogP). ...[more]

PMID: 24900257

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