A novel synthesis of 7-aryl-8-fluoro-pyrrolo[1,2-a]pyrimid-4-ones as potent, stable GnRH receptor antagonists

Bioorg Med Chem Lett. 2002 Dec 2;12(23):3491-5. doi: 10.1016/s0960-894x(02)00745-x.

Abstract

A new class of small molecule GnRH antagonists, the 7-aryl-8-fluoro-pyrrolo[1,2-a]pyrimid-4-ones, was designed and a novel synthesis for these compounds was developed. The synthesis utilizes a base-catalyzed intramolecular cyclization of fluoromethyl pyrimidone 5 to generate the bicyclic core. Amongst the compounds synthesized, we discovered some highly potent GnRH receptor antagonists (e.g., 12, K(i)=9 nM), which showed enhanced stability towards acidic physiological conditions compared to the des-fluoro analogues.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Calcium / metabolism
  • Cell Line
  • Cyclization
  • Drug Stability
  • Humans
  • Models, Molecular
  • Protein Binding
  • Pyrimidinones / chemistry*
  • Pyrimidinones / pharmacology*
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology*
  • Receptors, LHRH / antagonists & inhibitors*
  • Receptors, LHRH / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship
  • Thermodynamics

Substances

  • Pyrimidinones
  • Pyrroles
  • Receptors, LHRH
  • Recombinant Proteins
  • Calcium