title: Improving the developability profile of pyrrolidine progesterone receptor partial agonists.
abstract: The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.
authors.affiliation: Department of Chemistry, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA. lara.s.kallander@gsk.com
authors.forename: Lara S
authors.initials: LS
authors.lastname: Kallander
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: Patrick
authors.initials: P
authors.lastname: Stoy
authors.forename: Latisha
authors.initials: L
authors.lastname: Johnson
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.forename: Marlys
authors.initials: M
authors.lastname: Hammond
authors.forename: Linda S
authors.initials: LS
authors.lastname: Barton
authors.forename: Jaclyn R
authors.initials: JR
authors.lastname: Patterson
authors.forename: Leonard M
authors.initials: LM
authors.lastname: Azzarano
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nagilla
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Madauss
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Williams
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Stewart
authors.forename: Chaya
authors.initials: C
authors.lastname: Duraiswami
authors.forename: Eugene T
authors.initials: ET
authors.lastname: Grygielko
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Xu
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Laping
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Bray
authors.forename: Scott K
authors.initials: SK
authors.lastname: Thompson
mesh_terms: D000818:Animals; D001665:Binding Sites; D002219:Carbamates / Q000737:chemistry; D018360:Crystallography, X-Ray; D000072237:ERG1 Potassium Channel; D004715:Endometriosis / Q000188:drug therapy; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005260:Female; D006801:Humans; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D011980:Receptors, Progesterone / Q000819:agonists* / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D002219:Carbamates; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D011759:Pyrrolidines; D011980:Receptors, Progesterone; D013449:Sulfonamides; C032519:pyrrolidine