Discovery of orally active, pyrrolidinone-based progesterone receptor partial agonists

We have designed and synthesized a novel series of pyrrolidinones as progesterone receptor partial agonists. Compounds from this series had improved AR selectivity, rat pharmacokinetic properties, and in vivo potency compared to the lead compound. In addition, these compounds had improved selectivit...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-08, Vol.19 (16), p.4664-4668
Hauptverfasser:	Washburn, David G., Hoang, Tram H., Frazee, James S., Johnson, Latisha, Hammond, Marlys, Manns, Sharada, Madauss, Kevin P., Williams, Shawn P., Duraiswami, Chaya, Tran, Thuy B., Stewart, Eugene L., Grygielko, Eugene T., Glace, Lindsay E., Trizna, Walter, Nagilla, Rakesh, Bray, Jeffrey D., Thompson, Scott K.
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Agonist Androgen receptor Animals Binding Sites Biological and medical sciences Drug Discovery Endometriosis Ether-A-Go-Go Potassium Channels - metabolism Genital system. Reproduction Haplorhini hERG binding Hormone receptors Hormones. Endocrine system Humans Medical sciences Nuclear receptors OVX rat model Partial agonist Pharmacology. Drug treatments Progesterone receptor Progestin Pyrrolidinones - chemical synthesis Pyrrolidinones - chemistry Pyrrolidinones - pharmacokinetics Rats Receptors, Progesterone - agonists Receptors, Progesterone - metabolism Structure-Activity Relationship
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Beschreibung
Zusammenfassung:	We have designed and synthesized a novel series of pyrrolidinones as progesterone receptor partial agonists. Compounds from this series had improved AR selectivity, rat pharmacokinetic properties, and in vivo potency compared to the lead compound. In addition, these compounds had improved selectivity against hERG channel inhibition. We have designed and synthesized a novel series of pyrrolidinones as progesterone receptor partial agonists. Compounds from this series had improved AR selectivity, rat pharmacokinetic properties, and in vivo potency compared to the lead compound. In addition, these compounds had improved selectivity against hERG channel inhibition.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.06.081