Discovery of Acyl-sulfonamide Na v 1.7 Inhibitors GDC-0276 and GDC-0310

作者：Brian S. Safina, Steven J. McKerrall, Shaoyi Sun, Chien‐An Chen, Sultan Chowdhury, Qi Jia, Jun Li, Alla Zenova, Jean‐Christophe Andrez, Girish Bankar, Philippe Bergeron, Jae H. Chang, Elaine Chang, Jun Chen, Richard A. Dean, Shannon Decker, Antonio G. DiPasquale, Thilo Focken, Ivan Hemeon, Kuldip Khakh, Amy Kim, Rainbow Kwan, Andrea Lindgren, Sophia Lin, Jonathan Maher, Janette Mezeyova, Dinah Misner, Karen Nelkenbrecher, Jodie Pang, Rebecca M. Reese, Shannon D. Shields, Luis Sojo, Tao Sheng, Henry Verschoof, Matthew Waldbrook, Michael Wilson, Zhiwei Xie, Clint Young, Tanja S. Zabka, David H. Hackos, Daniel F. Ortwine, Andrew D. White, J. P. Johnson, Carole Robinette, Christoph M. Dehnhardt, Charles J. Cohen, Daniel P. Sutherlin · 发表于：Journal of Medicinal Chemistry · 年份：2021 · DOI：10.1021/acs.jmedchem.1c00049 · 被引用次数：42 · 研究领域：Ion channel regulation and function、Cardiac electrophysiology and arrhythmias、Cholinesterase and Neurodegenerative Diseases

Na v 1.7 is an extensively investigated target for pain with a strong genetic link in humans, yet in spite of this effort, it remains challenging to identify efficacious, selective, and safe inhibitors. Here, we disclose the discovery and preclinical profile of GDC-0276 ( 1 ) and GDC-0310 ( 2 ), selective Na v 1.7 inhibitors that have completed Phase 1 trials. Our initial search focused on close-in analogues to early compound 3 . This resulted in the discovery of GDC-0276 ( 1 ), which possessed improved metabolic stability and an acceptable overall pharmacokinetics profile. To further derisk the predicted human pharmacokinetics and enable QD dosing, additional optimization of the scaffold was conducted, resulting in the discovery of a novel series of N-benzyl piperidine Na v 1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 ( 2 ), which possesses improved Na v selectivity and pharmacokinetic profile over 1 .