title: Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists.
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.
authors: Department of Chemistry, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA.
authors: Scott K
authors: SK
authors: Thompson
authors: David G
authors: DG
authors: Washburn
authors: James S
authors: JS
authors: Frazee
authors: Kevin P
authors: KP
authors: Madauss
authors: Tram H
authors: TH
authors: Hoang
authors: Leahann
authors: L
authors: Lapinski
authors: Eugene T
authors: ET
authors: Grygielko
authors: Lindsay E
authors: LE
authors: Glace
authors: Walter
authors: W
authors: Trizna
authors: Shawn P
authors: SP
authors: Williams
authors: Chaya
authors: C
authors: Duraiswami
authors: Jeffrey D
authors: JD
authors: Bray
authors: Nicholas J
authors: NJ
authors: Laping
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D023421:Models, Animal; D017434:Protein Structure, Tertiary; D011759:Pyrrolidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D011980:Receptors, Progesterone / Q000819:agonists* / Q000378:metabolism
chemical_list: D011759:Pyrrolidines; D011980:Receptors, Progesterone; C032519:pyrrolidine