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)

  • J Med Chem. 2013 Nov 27;56(22):9351-5. doi: 10.1021/jm4013246.
Patrick R Gentry  1 ,  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
Affiliations
  • 1. Department of Pharmacology, ‡Vanderbilt Center for Neuroscience Drug Discovery, and §Vanderbilt Specialized Chemistry Center for Accelerated Probe Development (MLPCN), Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
PMID: 24164599 DOI: 10.1021/jm4013246
Abstract

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.

Products