Literature DB >> 24900257

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

Scott E Lazerwith1, Gina Bahador1, Eda Canales1, Guofeng Cheng1, Lee Chong1, Michael O Clarke1, Edward Doerffler1, Eugene J Eisenberg1, Jaclyn Hayes1, Bing Lu1, Qi Liu1, Mike Matles1, Michael Mertzman1, Michael L Mitchell1, Philip Morganelli1, Bernard P Murray1, Margaret Robinson1, Robert G Strickley1, Megan Tessler1, Neeraj Tirunagari1, Jianhong Wang1, Yujin Wang1, Jennifer R Zhang1, Xubin Zheng1, Weidong Zhong1, William J Watkins1.   

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).

Entities:  

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

Year:  2011        PMID： 24900257      PMCID： PMC4018142          DOI： 10.1021/ml200163b

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  11 in total

Review 1.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.

Authors:  C A Lipinski; F Lombardo; B W Dominy; P J Feeney
Journal:  Adv Drug Deliv Rev       Date:  2001-03-01       Impact factor: 15.470

2.  Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption.

Authors:  D E Clark
Journal:  J Pharm Sci       Date:  1999-08       Impact factor: 3.534

3.  Prediction of drug absorption using multivariate statistics.

Authors:  W J Egan; K M Merz; J J Baldwin
Journal:  J Med Chem       Date:  2000-10-19       Impact factor: 7.446

Review 4.  Prediction of intestinal permeability.

Authors:  William J Egan; Georgio Lauri
Journal:  Adv Drug Deliv Rev       Date:  2002-03-31       Impact factor: 15.470

5.  Time-related differences in the physical property profiles of oral drugs.

Authors:  Paul D Leeson; Andrew M Davis
Journal:  J Med Chem       Date:  2004-12-02       Impact factor: 7.446

6.  A bioavailability score.

Authors:  Yvonne C Martin
Journal:  J Med Chem       Date:  2005-05-05       Impact factor: 7.446

7.  ADME evaluation in drug discovery. 7. Prediction of oral absorption by correlation and classification.

Authors:  Tingjun Hou; Junmei Wang; Wei Zhang; Xiaojie Xu
Journal:  J Chem Inf Model       Date:  2007 Jan-Feb       Impact factor: 4.956

Review 8.  The influence of drug-like concepts on decision-making in medicinal chemistry.

Authors:  Paul D Leeson; Brian Springthorpe
Journal:  Nat Rev Drug Discov       Date:  2007-11       Impact factor: 84.694

9.  Molecular properties that influence the oral bioavailability of drug candidates.

Authors:  Daniel F Veber; Stephen R Johnson; Hung-Yuan Cheng; Brian R Smith; Keith W Ward; Kenneth D Kopple
Journal:  J Med Chem       Date:  2002-06-06       Impact factor: 7.446

Review 10.  Epidemiology of HCV infection.

Authors:  V Baldo; T Baldovin; R Trivello; A Floreani
Journal:  Curr Pharm Des       Date:  2008       Impact factor: 3.116
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  2 in total

1.  Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1).

Authors:  Catherine White; Meredeth A McGowan; Hua Zhou; Nunzio Sciammetta; Xavier Fradera; Jongwon Lim; Elizabeth M Joshi; Christine Andrews; Elliott B Nickbarg; Phillip Cowley; Sarah Trewick; Martin Augustin; Konstanze von Köenig; Charles A Lesburg; Karin Otte; Ian Knemeyer; Hyun Woo; Wensheng Yu; Mangeng Cheng; Peter Spacciapoli; Prasanthi Geda; Xuelei Song; Nadya Smotrov; Patrick Curran; Mee Ra Heo; Pravien Abeywickrema; J Richard Miller; David Jonathan Bennett; Yongxin Han
Journal:  ACS Med Chem Lett       Date:  2020-03-10       Impact factor: 4.345

2.  Carbamate and N-Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.

Authors:  Derun Li; Yongqi Deng; Abdelghani Achab; Indu Bharathan; Brett Andrew Hopkins; Wensheng Yu; Hongjun Zhang; Sulagna Sanyal; Qinglin Pu; Hua Zhou; Kun Liu; Jongwon Lim; Xavier Fradera; Charles A Lesburg; Alfred Lammens; Theodore A Martinot; Ryan D Cohen; Amy C Doty; Heidi Ferguson; Elliott B Nickbarg; Mangeng Cheng; Peter Spacciapoli; Prasanthi Geda; Xuelei Song; Nadya Smotrov; Pravien Abeywickrema; Christine Andrews; Chad Chamberlin; Omar Mabrouk; Patrick Curran; Matthew Richards; Peter Saradjian; J Richard Miller; Ian Knemeyer; Karin M Otte; Stella Vincent; Nunzio Sciammetta; Alexander Pasternak; David Jonathan Bennett; Yongxin Han
Journal:  ACS Med Chem Lett       Date:  2021-02-26       Impact factor: 4.345
  2 in total

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