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

…, E Doerffler, EJ Eisenberg, J Hayes, B Lu…

Index: Lazerwith, Scott E.; Bahador, Gina; Canales, Eda; Cheng, Guofeng; Chong, Lee; Clarke, Michael O.; Doerffler, Edward; Eisenberg, Eugene J.; Hayes, Jaclyn; Lu, Bing; Liu, Qi; Matles, Mike; Mertzman, Michael; Mitchell, Michael L.; Morganelli, Philip; Murray, Bernard P.; Robinson, Margaret; Strickley, Robert G.; Tessler, Megan; Tirunagari, Neeraj; Wang, Jianhong; Wang, Yujin; Zhang, Jennifer R.; Zheng, Xubin; Zhong, Weidong; Watkins, William J. ACS Medicinal Chemistry Letters, 2011 , vol. 2, # 10 p. 715 - 719

Full Text: HTML

Citation Number: 8

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).