1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as potent GR antagonists with reduced hERG inhibition and an improved pharmacokinetic profile

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 24; pp. 5720 - 5725
• Main Authors: Hunt, Hazel J., Belanoff, Joseph K., Golding, Emily, Gourdet, Benoit, Phillips, Timothy, Swift, Denise, Thomas, Jennifer, Unitt, John F., Walters, Iain
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2015; Elsevier
• Subjects: 1H-Pyrazolo[3,4-g]hexahydro-isoquinolines; Animals; Binding Sites; Catalytic Domain; Cell Line; Chemistry; Chemistry, Medicinal; Chemistry, Organic; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Ether-A-Go-Go Potassium Channels - metabolism; Glucocorticoid receptor antagonists; Hep G2 Cells; hERG inhibition; Humans; Insulin resistance; Isoquinolines - chemistry; Isoquinolines - metabolism; Life Sciences & Biomedicine; Molecular Docking Simulation; Pharmacology & Pharmacy; Physical Sciences; Protein Binding; Pyrazoles - chemistry; Rats; Receptors, Glucocorticoid - antagonists & inhibitors; Receptors, Glucocorticoid - metabolism; Science & Technology; Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - metabolism; Insulin resistance; hERG inhibition; 1H-Pyrazolo[3,4-g]hexahydro-isoquinolines; Glucocorticoid receptor antagonists; DISEASE; HEALTH; GLUCOCORTICOID-RECEPTOR MODULATOR
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.10.097

[Display omitted] 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.