title: Discovery of orally active, pyrrolidinone-based progesterone receptor partial agonists.
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.
authors.affiliation: Department of Chemistry, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA 19406, USA. dave.g.washburn@gsk.com
authors.forename: David G
authors.initials: DG
authors.lastname: Washburn
authors.forename: Tram H
authors.initials: TH
authors.lastname: Hoang
authors.forename: James S
authors.initials: JS
authors.lastname: Frazee
authors.forename: Latisha
authors.initials: L
authors.lastname: Johnson
authors.forename: Marlys
authors.initials: M
authors.lastname: Hammond
authors.forename: Sharada
authors.initials: S
authors.lastname: Manns
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Madauss
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Williams
authors.forename: Chaya
authors.initials: C
authors.lastname: Duraiswami
authors.forename: Thuy B
authors.initials: TB
authors.lastname: Tran
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Stewart
authors.forename: Eugene T
authors.initials: ET
authors.lastname: Grygielko
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Glace
authors.forename: Walter
authors.initials: W
authors.lastname: Trizna
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nagilla
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Bray
authors.forename: Scott K
authors.initials: SK
authors.lastname: Thompson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D055808:Drug Discovery; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D011980:Receptors, Progesterone / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D011760:Pyrrolidinones; D011980:Receptors, Progesterone