Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists.
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.
Thompson
Scott K
SK
Department of Chemistry, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA.
Washburn
David G
DG
Frazee
James S
JS
Madauss
Kevin P
KP
Hoang
Tram H
TH
Lapinski
Leahann
L
Grygielko
Eugene T
ET
Glace
Lindsay E
LE
Trizna
Walter
W
Williams
Shawn P
SP
Duraiswami
Chaya
C
Bray
Jeffrey D
JD
Laping
Nicholas J
NJ
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
D011759:Pyrrolidines; D011980:Receptors, Progesterone; C032519:pyrrolidine