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. 2011 Aug 8;2(10):715-9.
doi: 10.1021/ml200163b. eCollection 2011 Oct 13.

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

Scott E Lazerwith  1 , Gina Bahador  1 , Eda Canales  1 , Guofeng Cheng  1 , Lee Chong  1 , Michael O Clarke  1 , Edward Doerffler  1 , Eugene J Eisenberg  1 , Jaclyn Hayes  1 , Bing Lu  1 , Qi Liu  1 , Mike Matles  1 , Michael Mertzman  1 , Michael L Mitchell  1 , Philip Morganelli  1 , Bernard P Murray  1 , Margaret Robinson  1 , Robert G Strickley  1 , Megan Tessler  1 , Neeraj Tirunagari  1 , Jianhong Wang  1 , Yujin Wang  1 , Jennifer R Zhang  1 , Xubin Zheng  1 , Weidong Zhong  1 , William J Watkins  1
Affiliations

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

Scott E Lazerwith et al. ACS Med Chem Lett. .

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).

Keywords: 3*HBD-cLogP; HCV inhibitors; Pharmacokinetics; pyrido[3,2-d]pyrimidine core.

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Figures

Figure 1
Figure 1
Relationship between rat bioavailability and PSA.
Figure 2
Figure 2
Example of increased PSA leading to reduced bioavailability.
Figure 3
Figure 3
Relationship between MRT in the rat and cLogP.
Figure 4
Figure 4
Examples of the association between MRT in the rat and cLogP.
Figure 5
Figure 5
Two subseries in which PK was optimized through manipulation of PSA and cLogP.
Figure 6
Figure 6
IV and oral rat PK for compound 2.
Figure 7
Figure 7
Relationship between % F (rat) and HBA count for analogues with PSA 140–160.
Figure 8
Figure 8
Relationship between % F (rat) and HBD count for analogues with PSA 140–160.
Figure 9
Figure 9
Example of a pair of high PSA analogues in which % F was improved by an increase in lipophilicity.
Figure 10
Figure 10
Relationship between % F (rat) and 3*HBD-cLogP for analogues with PSA 140–160.
Figure 11
Figure 11
Relationship between % F (rat) and 3*HBD-cLogP for all of the pyridopyrimidines.
See this image and copyright information in PMC

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