2. Academic Validation
  3. 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)

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

Affiliation

  • 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.

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