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. Epub 2013 Nov 13.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

  • 9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo(2,1-a)isoindol-5(9bH)-one
  • Imidazoles
  • Indoles
  • Receptor, Muscarinic M5