Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375)

Research output: Contribution to journalJournal articleResearchpeer-review

  • Gentry, Patrick Ryan
  • Masaya Kokubo
  • Thomas M Bridges
  • Nathan R Kett
  • Joel M Harp
  • Hyekyung P Cho
  • Emery Smith
  • Peter Chase
  • Peter S Hodder
  • Colleen M Niswender
  • J Scott Daniels
  • P Jeffrey Conn
  • Michael R Wood
  • Craig W Lindsley

A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) negative allosteric modulator (NAM) selective for the M5 subtype. ML375 is a highly selective M5 NAM with submicromolar potency (human M5 IC50 = 300 nM, rat M5 IC50 = 790 nM, M1-M4 IC50 > 30 μM), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Issue number22
Pages (from-to)9351-5
Number of pages5
Publication statusPublished - 27 Nov 2013
Externally publishedYes

    Research areas

  • Allosteric Regulation/drug effects, Animals, Brain/drug effects, CHO Cells, Cricetinae, Cricetulus, Drug Discovery, Drug Evaluation, Preclinical, Humans, Imidazoles/chemistry, Indoles/chemistry, Male, Rats, Receptor, Muscarinic M5/chemistry, Structure-Activity Relationship, Substrate Specificity

ID: 213599951