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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| Published in | Bioorganic & medicinal chemistry letters Vol. 19; no. 16; pp. 4777 - 4780 |
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| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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Amsterdam
Elsevier Ltd
15.08.2009
Elsevier |
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| 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.
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. |
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| AbstractList | 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. 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. |
| Author | Lapinski, Leahann Hoang, Tram H. Duraiswami, Chaya Trizna, Walter Williams, Shawn P. Madauss, Kevin P. Laping, Nicholas J. Frazee, James S. Grygielko, Eugene T. Bray, Jeffrey D. Thompson, Scott K. Washburn, David G. Glace, Lindsay E. |
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| Cites_doi | 10.1038/30775 10.1021/jm030640n 10.1093/emboj/18.17.4608 10.1210/me.2002-0438 10.1016/S0960-0760(01)00091-7 10.1126/science.280.5370.1747 10.1210/me.2006-0524 10.1517/14728214.11.3.503 10.1210/edrv-11-2-266 |
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| Keywords | 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 |
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| SubjectTerms | 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 |
| Title | Rational design of orally-active, pyrrolidine-based progesterone receptor partial agonists |
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