Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges

Bioorg Med Chem Lett. 2015 Feb 1;25(3):690-4. doi: 10.1016/j.bmcl.2014.11.082. Epub 2014 Dec 13.

Abstract

This Letter describes the continued optimization of the MLPCN probe ML375, a highly selective M5 negative allosteric modulator (NAM), through a combination of matrix libraries and iterative parallel synthesis. True to certain allosteric ligands, SAR was shallow, and the matrix library approach highlighted the challenges with M5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M5 were improved over ML375, along with slight enhancement in physiochemical properties, certain in vitro DMPK parameters and CNS distribution. Attempts to further enhance pharmacokinetics with deuterium incorporation afforded mixed results, but pretreatment with a pan-P450 inhibitor (1-aminobenzotriazole; ABT) provided increased plasma exposure.

Keywords: M(5); Matrix library; Muscarinic receptor; Negative allosteric modulator; Pharmacokinetics.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Animals
  • Brain / metabolism
  • Half-Life
  • Humans
  • Imidazoles / chemistry*
  • Imidazoles / metabolism
  • Imidazoles / pharmacokinetics
  • Indoles / chemistry*
  • Indoles / metabolism
  • Indoles / pharmacokinetics
  • Microsomes, Liver / metabolism
  • Protein Binding
  • Rats
  • Receptor, Muscarinic M5 / chemistry*
  • Receptor, Muscarinic M5 / genetics
  • Receptor, Muscarinic M5 / metabolism
  • Structure-Activity Relationship

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