Discovery of AAT-008, a novel, potent, and selective prostaglandin EP4 receptor antagonist

Bioorg Med Chem Lett. 2017 Mar 1;27(5):1186-1192. doi: 10.1016/j.bmcl.2017.01.067. Epub 2017 Jan 25.

Abstract

Starting from acylsufonamide HTS hit 2, a novel series of para-N-acylaminomethylbenzoic acids was identified and developed as selective prostaglandin EP4 receptor antagonists. Structural modifications on lead compound 4a were explored with the aim of improving potency, physicochemical properties, and animal PK predictive of QD (once a day) dosing regimen in human. These efforts led to the discovery of the clinical candidate AAT-008 (4j), which exhibited significantly improved pharmacological profiles over grapiprant (1).

Keywords: Autoimmune diseases; Cancer; Clinical candidate; EP4 receptor antagonist; Inflammation; Pain; Prostaglandin E2; Structure–activity relationship (SAR).

MeSH terms

  • Animals
  • Benzoates / chemistry
  • Benzoates / pharmacokinetics
  • Benzoates / pharmacology*
  • Drug Discovery
  • Humans
  • Niacinamide / analogs & derivatives*
  • Niacinamide / chemistry
  • Niacinamide / pharmacokinetics
  • Niacinamide / pharmacology
  • Prostaglandin Antagonists / chemistry
  • Prostaglandin Antagonists / pharmacokinetics
  • Prostaglandin Antagonists / pharmacology*
  • Receptors, Prostaglandin E, EP4 Subtype / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • AAT-008
  • Benzoates
  • Prostaglandin Antagonists
  • Receptors, Prostaglandin E, EP4 Subtype
  • Niacinamide