Discovery of novel, potent, selective, and orally active human glucagon receptor antagonists containing a pyrazole core

Bioorg Med Chem Lett. 2011 Jan 1;21(1):76-81. doi: 10.1016/j.bmcl.2010.11.074. Epub 2010 Nov 21.

Abstract

A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10 mpk, respectively.

MeSH terms

  • Administration, Oral
  • Animals
  • Blood Glucose / metabolism
  • Dogs
  • Drug Evaluation, Preclinical
  • Humans
  • Macaca mulatta
  • Mice
  • Mice, Transgenic
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacokinetics
  • Rats
  • Receptors, Glucagon / antagonists & inhibitors*
  • Receptors, Glucagon / metabolism
  • Structure-Activity Relationship

Substances

  • Blood Glucose
  • Pyrazoles
  • Receptors, Glucagon