Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists

Bioorg Med Chem Lett. 2009 Aug 15;19(16):4777-80. doi: 10.1016/j.bmcl.2009.06.055. Epub 2009 Jun 17.

Abstract

Using the X-ray crystal structure of an amide-based progesterone receptor (PR) partial agonist bound to the PR ligand binding domain, a novel PR partial agonist class containing a pyrrolidine ring was designed. Members of this class of N-alkylpyrrolidines demonstrate potent and highly selective partial agonism of the progesterone receptor, and one of these analogs was shown to be efficacious upon oral dosing in the OVX rat model of estrogen opposition.

MeSH terms

  • Administration, Oral
  • Animals
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Drug Design
  • Models, Animal
  • Protein Structure, Tertiary
  • Pyrrolidines / administration & dosage
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry*
  • Rats
  • Receptors, Progesterone / agonists*
  • Receptors, Progesterone / metabolism

Substances

  • Pyrrolidines
  • Receptors, Progesterone
  • pyrrolidine