title: 1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as potent GR antagonists with reduced hERG inhibition and an improved pharmacokinetic profile.
abstract: We report the further optimization of our series 1H-pyrazolo[3,4-g]hexahydro-isoquinoline sulfonamides as GR antagonists. By incorporating a heteroaryl ketone group at the ring junction, we have obtained compounds with excellent functional GR antagonism. Optimization of the sulfonamide substituent has provided compounds with a very desirable overall profile, including minimal hERG activity, good bioavailability and in vivo efficacy.
authors.affiliation: Corcept Therapeutics, 149 Commonwealth Drive, Menlo Park, CA 94025, USA. Electronic address: hhunt@corcept.com.
authors.forename: Hazel J
authors.initials: HJ
authors.lastname: Hunt
authors.affiliation: Corcept Therapeutics, 149 Commonwealth Drive, Menlo Park, CA 94025, USA.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Belanoff
authors.affiliation: Sygnature Discovery, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Golding
authors.affiliation: Sygnature Discovery, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
authors.forename: Benoit
authors.initials: B
authors.lastname: Gourdet
authors.affiliation: Sygnature Discovery, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Phillips
authors.affiliation: Sygnature Discovery, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
authors.forename: Denise
authors.initials: D
authors.lastname: Swift
authors.affiliation: Sygnature Discovery, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Sygnature Discovery, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: Unitt
authors.affiliation: Sygnature Discovery, BioCity, Pennyfoot Street, Nottingham NG1 1GF, UK.
authors.forename: Iain
authors.initials: I
authors.lastname: Walters
mesh_terms: D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007546:Isoquinolines; C000606913:KCNH2 protein, human; D011720:Pyrazoles; D011965:Receptors, Glucocorticoid; D013449:Sulfonamides; C039109:isoquinoline
keywords: 1H-Pyrazolo[3,4-g]hexahydro-isoquinolines; Glucocorticoid receptor antagonists; Insulin resistance; hERG inhibition