Enhancement of pharmacokinetic properties and in vivo efficacy of benzylidene ketal M(2) muscarinic receptor antagonists via benzamide modification

Bioorg Med Chem Lett. 2002 Dec 2;12(23):3479-82. doi: 10.1016/s0960-894x(02)00742-4.

Abstract

We previously reported the initial discovery of a novel class of stabilized benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues consisting of benzamide modifications which not only improved M(2) receptor affinity and selectivity, but also enhanced the pharmacokinetic properties of the series. These changes led to the discovery of a highly potent and selective M(2) antagonist, which demonstrated in vivo efficacy and had good bioavailability in multiple species.

MeSH terms

  • Acetylcholine / analysis
  • Acetylcholine / biosynthesis
  • Animals
  • Area Under Curve
  • Benzamides / chemistry*
  • Benzamides / pharmacology
  • Benzylidene Compounds / chemistry*
  • Benzylidene Compounds / pharmacokinetics*
  • Drug Design
  • Drug Evaluation, Preclinical
  • Humans
  • Microdialysis
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Muscarinic Antagonists / chemistry*
  • Muscarinic Antagonists / pharmacology*
  • Rats
  • Receptors, Muscarinic / drug effects*
  • Receptors, Muscarinic / metabolism
  • Structure-Activity Relationship

Substances

  • Benzamides
  • Benzylidene Compounds
  • Muscarinic Antagonists
  • Receptors, Muscarinic
  • Acetylcholine