Literature DB >> 25542588

Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges.

Haruto Kurata1, Patrick R Gentry1, Masaya Kokubo1, Hyekyung P Cho2, Thomas M Bridges2, Colleen M Niswender2, Frank W Byers2, Michael R Wood2, J Scott Daniels2, P Jeffrey Conn2, Craig W Lindsley3.   

Abstract

This Letter describes the continued optimization of the MLPCN probe ML375, a highly selective M5 negative allosteric modulator (NAM), through a combination of matrix libraries and iterative parallel synthesis. True to certain allosteric ligands, SAR was shallow, and the matrix library approach highlighted the challenges with M5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M5 were improved over ML375, along with slight enhancement in physiochemical properties, certain in vitro DMPK parameters and CNS distribution. Attempts to further enhance pharmacokinetics with deuterium incorporation afforded mixed results, but pretreatment with a pan-P450 inhibitor (1-aminobenzotriazole; ABT) provided increased plasma exposure.
Copyright © 2014 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  M(5); Matrix library; Muscarinic receptor; Negative allosteric modulator; Pharmacokinetics

Mesh：

Substances：

Year:  2014        PMID： 25542588      PMCID： PMC4535335          DOI： 10.1016/j.bmcl.2014.11.082

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  25 in total

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