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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Haruto Kurata
  • Gentry, Patrick Ryan
  • Masaya Kokubo
  • Hyekyung P Cho
  • Thomas M Bridges
  • Colleen M Niswender
  • Frank W Byers
  • Michael R Wood
  • J Scott Daniels
  • P Jeffrey Conn
  • Craig W Lindsley

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.

Original languageEnglish
JournalBioorganic & Medicinal Chemistry Letters
Issue number3
Pages (from-to)690-4
Number of pages5
Publication statusPublished - 1 Feb 2015
Externally publishedYes

Bibliographical note

Copyright © 2014 Elsevier Ltd. All rights reserved.

    Research areas

  • Allosteric Regulation, Animals, Brain/metabolism, Half-Life, Humans, Imidazoles/chemistry, Indoles/chemistry, Microsomes, Liver/metabolism, Protein Binding, Rats, Receptor, Muscarinic M5/chemistry, Structure-Activity Relationship

ID: 213599333