Discovery of a novel 2-(1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole derivative as an EP1 receptor antagonist and in vivo studies in a bone fracture model

Bioorg Med Chem Lett. 2018 Aug 1;28(14):2408-2412. doi: 10.1016/j.bmcl.2018.06.022. Epub 2018 Jun 19.

Abstract

We describe a medicinal chemistry approach to the discovery of a novel EP1 antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1, an EP1 receptor antagonist that exhibits pharmacological efficacy in cystometry models following intravenous administration. Despite its good potency in vitro, the high lipophilicity of 1 is a concern in long-term in vivo studies. Further medicinal chemistry efforts identified 4 as an improved lead compound with good in vitro ADME profile applicable to long term in vivo studies. A rat fracture study was conducted with 4 for 4 weeks to validate its utility in bone fracture healing. The results suggest that this EP1 receptor antagonist stimulates callus formation and thus 4 has potential for enhancing fracture healing.

Keywords: Bone fracture healing; EP(1) receptor; Oral administration; Prostaglandin E(2); Target validation.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Fracture Healing / drug effects*
  • Fractures, Bone / drug therapy*
  • Fractures, Bone / metabolism
  • Madin Darby Canine Kidney Cells / drug effects
  • Madin Darby Canine Kidney Cells / metabolism
  • Madin Darby Canine Kidney Cells / pathology
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • Receptors, Prostaglandin E, EP1 Subtype / antagonists & inhibitors*
  • Receptors, Prostaglandin E, EP1 Subtype / deficiency
  • Receptors, Prostaglandin E, EP1 Subtype / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*

Substances

  • Receptors, Prostaglandin E, EP1 Subtype
  • Thiazoles