학술논문
Structure- and Ligand-Based Discovery of Chromane Arylsulfonamide Nav1.7 Inhibitors for the Treatment of Chronic Pain
Document Type
Article
Author
McKerrall, Steven J.; Nguyen, Teresa; Lai, Kwong Wah; Bergeron, Philippe; Deng, Lunbin; DiPasquale, Antonio; Chang, Jae H.; Chen, Jun; Chernov-Rogan, Tania; Hackos, David H.; Maher, Jonathan; Ortwine, Daniel F.; Pang, Jodie; Payandeh, Jian; Proctor, William R.; Shields, Shannon D.; Vogt, Jennifer; Ji, Pengfei; Liu, Wenfeng; Ballini, Elisa; Schumann, Lilia; Tarozzo, Glauco; Bankar, Girish; Chowdhury, Sultan; Hasan, Abid; Johnson, J. P.; Khakh, Kuldip; Lin, Sophia; Cohen, Charles J.; Dehnhardt, Christoph M.; Safina, Brian S.; Sutherlin, Daniel P.
Source
Journal of Medicinal Chemistry; April 2019, Vol. 62 Issue: 8 p4091-4109, 19p
Subject
Language
ISSN
00222623; 15204804
Abstract
Using structure- and ligand-based design principles, a novel series of piperidyl chromane arylsulfonamide Nav1.7 inhibitors was discovered. Early optimization focused on improvement of potency through refinement of the low energy ligand conformation and mitigation of high in vivo clearance. An in vitro hepatotoxicity hazard was identified and resolved through optimization of lipophilicity and lipophilic ligand efficiency to arrive at GNE-616 (24), a highly potent, metabolically stable, subtype selective inhibitor of Nav1.7. Compound 24showed a robust PK/PD response in a Nav1.7-dependent mouse model, and site-directed mutagenesis was used to identify residues critical for the isoform selectivity profile of 24.