Novel pyrazolo[1,5-a]pyridines as orally active EP1 receptor antagonists: Synthesis, structure-activity relationship studies, and biological evaluation

Bioorg Med Chem. 2017 May 1;25(9):2635-2642. doi: 10.1016/j.bmc.2017.03.003. Epub 2017 Mar 14.

Abstract

Novel pyrazolo[1,5-a]pyridine derivatives were designed, synthesized and evaluated as orally active EP1 antagonists for the treatment of overactive bladder. Matched molecular pair analysis (MMPA) allowed the design of a new series of pyrazolo[1,5-a]pyridine derivatives 4-6. Structure-activity relationships (SAR) studies of 4-6 were performed, leading to identification of the nanomolar-level EP1 antagonist 4c, which exhibited good pharmacological effect through intraduodenal (id) administration in a 17-phenyltrinor prostaglandin E2-induced bladder contraction model in rats.

Keywords: EP(1) antagonist; Matched molecular pair; Pyrazolo[1,5-a]pyridine; Structure-activity relationships.

MeSH terms

  • Animals
  • Cell Line
  • Male
  • Pyrazoles / chemical synthesis
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / therapeutic use*
  • Pyridines / chemical synthesis
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use*
  • Rats, Wistar
  • Receptors, Prostaglandin E, EP1 Subtype / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Urinary Bladder, Overactive / drug therapy

Substances

  • 1-((5-chloro-2-phenylpyrazolo(1,5-a)pyridin-7-yl)methyl)-5-methyl-1H-pyrazole-3-carboxylic acid
  • Pyrazoles
  • Pyridines
  • Receptors, Prostaglandin E, EP1 Subtype