Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors

J Med Chem. 2016 Jan 14;59(1):194-205. doi: 10.1021/acs.jmedchem.5b01249. Epub 2015 Dec 18.

Abstract

As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 μM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8·H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / pharmacology*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Biological Availability
  • Celecoxib / pharmacology
  • Cyclooxygenase Inhibitors / chemical synthesis*
  • Cyclooxygenase Inhibitors / pharmacokinetics
  • Cyclooxygenase Inhibitors / pharmacology*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors / chemical synthesis
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology
  • Dogs
  • Drug Discovery
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacology*
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Microsomes / drug effects
  • Microsomes / enzymology*
  • Models, Molecular
  • Prostaglandin-E Synthases
  • Rats
  • Structure-Activity Relationship

Substances

  • Analgesics
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Imidazoles
  • Cytochrome P-450 CYP3A
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases
  • Celecoxib