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Discovery of orally active,pyrrolidinone-based progesterone receptor partial agonists
Authors:David G Washburn  Tram H Hoang  James S Frazee  Latisha Johnson  Marlys Hammond  Sharada Manns  Kevin P Madauss  Shawn P Williams  Chaya Duraiswami  Thuy B Tran  Eugene L Stewart  Eugene T Grygielko  Lindsay E Glace  Walter Trizna  Rakesh Nagilla  Jeffrey D Bray  Scott K Thompson
Institution:1. Department of Chemistry, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA;2. Department of Biology, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA;3. Department of Drug Metabolism and Pharmacokinetics, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA;4. Department of Computational and Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline Pharmaceuticals, PO Box 13398, Research Triangle Park, NC 27709, USA;5. Department of Computational and Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline Pharmaceuticals, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426, USA
Abstract: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.
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