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

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 16; pp. 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: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.08.2009; Elsevier
• 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; Partial agonist; Hormone receptors; Endometriosis; Agonist; Nuclear receptor; Progesterone receptor; Nitrile; Rat; Binding site; Modeling; Pyrrolidine derivatives; Chlorine Organic compounds; Molecular model; Uterine diseases; Benzonitrile derivatives; Chemical synthesis; Biological receptor; Rodentia; Oral administration; In vitro; Biological activity; Female genital diseases; In vivo; Vertebrata; Mammalia; Animal; Fluorine Organic compounds; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.06.055

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.