Development of novel M1 antagonist scaffolds through the continued optimization of the MLPCN probe ML012

Bioorg Med Chem Lett. 2012 Aug 1;22(15):5035-40. doi: 10.1016/j.bmcl.2012.06.018. Epub 2012 Jun 15.

Abstract

This Paper describes the continued optimization of an MLPCN probe molecule M(1) antagonist (ML012) through an iterative parallel synthesis approach. After several rounds of modifications of the parent compound, we arrived at a new azetidine scaffold that displayed improved potency while maintaining a desirable level of selectivity over other muscarinic receptor subtypes. Data for representative molecules 7w (VU0452865) and 12a (VU0455691) are presented.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azabicyclo Compounds / chemical synthesis
  • Azabicyclo Compounds / chemistry*
  • Azabicyclo Compounds / metabolism
  • Azetidines / chemical synthesis
  • Azetidines / chemistry*
  • Azetidines / metabolism
  • Cytochrome P-450 Enzyme System / metabolism
  • Humans
  • Molecular Probes / chemistry*
  • Protein Binding
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Rats
  • Receptor, Muscarinic M1 / antagonists & inhibitors*
  • Receptor, Muscarinic M1 / metabolism
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Thiadiazoles / chemistry*

Substances

  • Azabicyclo Compounds
  • Azetidines
  • Molecular Probes
  • N-(3-oxo-3-(4-(pyridin-4-yl)piperazin-1-yl)propyl)benzo(c)(1,2,5)thiadiazole-4-sulfonamide
  • Protein Isoforms
  • Receptor, Muscarinic M1
  • Sulfonamides
  • Thiadiazoles
  • VU0455691
  • azetidine
  • Cytochrome P-450 Enzyme System