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Literature DB >> 20510621

A statistical analysis of in vitro human microsomal metabolic stability of small phenyl group substituents, leading to improved design sets for parallel SAR exploration of a chemical series.

Abstract

An analysis of in vitro human liver microsomal turnover assay results from a large dataset ( approximately 75 K) of experimental compounds tested is presented. Combined with an analysis of small (<6 Ha) substituents on known drugs and existing published results a new set of 29 substituents (consensus) is proposed to increase stability and probe SAR (an enhanced 'Topliss set'). In addition a different group of 28 substituents are identified as unlikely to change in vitro HLM stability, and a further set of compounds focuses on increasing HLM stability only. Copyright 2010 Elsevier Ltd. All rights reserved.

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Year: 2010 PMID： 20510621 DOI： 10.1016/j.bmc.2010.04.077

Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641

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Cited

5 in total

Review 1. Chemical predictive modelling to improve compound quality.

Authors: John G Cumming; Andrew M Davis; Sorel Muresan; Markus Haeberlein; Hongming Chen
Journal: Nat Rev Drug Discov Date: 2013-12 Impact factor: 84.694

2. Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T-Type Calcium Channel Blocker, ABT-639.

Authors: Qingwei Zhang; Zhiren Xia; Shailen Joshi; Victoria E Scott; Michael F Jarvis
Journal: ACS Med Chem Lett Date: 2015-04-28 Impact factor: 4.345

A statistical analysis of in vitro human microsomal metabolic stability of small phenyl group substituents, leading to improved design sets for parallel SAR exploration of a chemical series.

Review 1. Chemical predictive modelling to improve compound quality.

2. Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T-Type Calcium Channel Blocker, ABT-639.

3. When Cofactors Aren't X Factors: Functional Groups That Are Labile in Human Liver Microsomes in the Absence of NADPH.

4. Elucidation of fluorine's impact on pK_a and in vitro Pgp-mediated efflux for a series of PDE9 inhibitors.

Review 5. Matched Molecular Pair Analysis in Short: Algorithms, Applications and Limitations.

A statistical analysis of in vitro human microsomal metabolic stability of small phenyl group substituents, leading to improved design sets for parallel SAR exploration of a chemical series.

Review 1. Chemical predictive modelling to improve compound quality.

2. Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T-Type Calcium Channel Blocker, ABT-639.

3. When Cofactors Aren't X Factors: Functional Groups That Are Labile in Human Liver Microsomes in the Absence of NADPH.

4. Elucidation of fluorine's impact on pKa and in vitro Pgp-mediated efflux for a series of PDE9 inhibitors.

Review 5. Matched Molecular Pair Analysis in Short: Algorithms, Applications and Limitations.

4. Elucidation of fluorine's impact on pK_a and in vitro Pgp-mediated efflux for a series of PDE9 inhibitors.