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 part...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-08, Vol.19 (16), p.4777-4780
Main Authors: Thompson, Scott K., Washburn, David G., Frazee, James S., Madauss, Kevin P., Hoang, Tram H., Lapinski, Leahann, Grygielko, Eugene T., Glace, Lindsay E., Trizna, Walter, Williams, Shawn P., Duraiswami, Chaya, Bray, Jeffrey D., Laping, Nicholas J.
Format: Article
Language:English
Subjects:
Administration, Oral
Agonist
Animals
Binding Sites
Biological and medical sciences
Computer Simulation
CRYSTAL STRUCTURE
Crystallography, X-Ray
DESIGN
Drug Design
Endometriosis
ESTROGENS
Genital system. Reproduction
Hormone receptors
Hormones. Endocrine system
MATERIALS SCIENCE
Medical sciences
Models, Animal
Nuclear receptor
Partial agonist
Pharmacology. Drug treatments
PROGESTERONE
Progesterone receptor
Protein Structure, Tertiary
PYRROLIDINES
Pyrrolidines - administration & dosage
Pyrrolidines - chemical synthesis
Pyrrolidines - chemistry
Rats
Receptors, Progesterone - agonists
Receptors, Progesterone - metabolism
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Summary: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. 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.06.055