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)

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

doi:10.1021/jm4013246

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)

Patrick R Gentry, Joel M Harp + Show 12 more

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https://doi.org/10.1021/jm4013246

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Journal: Journal of Medicinal Chemistry	Publication Date: Nov 13, 2013
Citations: 64

Affiliation: Vanderbilt University Medical Center, Scripps Research Institute

#High CNS Penetration #Functional High Throughput Screen + Show 8 more

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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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