Optimization of Pharmacokinetics through Manipulation of Physicochemical Properties in a Series of HCV Inhibitors
Scott E. Lazerwith, Gina Bahador, Eda Canales, Guofeng Cheng, Lee S. Chong, Michael O. Clarke, Edward M. Doerffler, Eugene J. Eisenberg, Jaclyn Hayes, Bing Lu, Qi Liu, Mike Matles, Michael Mertzman, Michael L. Mitchell, Philip Morganelli, Bernard P. Murray, Margaret F. Robinson, Robert G. Strickley, Megan Tessler, Neeraj Tirunagari · ACS Medicinal Chemistry Letters · 2011
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).