Discovery of Acyl-sulfonamide Nav1.7 Inhibitors GDC-0276 and GDC-0310

Autor: Sultan Chowdhury, Christoph Martin Dehnhardt, Tao Sheng, Clint Young, Rainbow Kwan, Michael Scott Wilson, Jun Chen, Matthew Waldbrook, Dinah Misner, C. Lee Robinette, Rebecca M. Reese, Elaine Chang, Henry Verschoof, Tanja S. Zabka, Girish Bankar, Philippe Bergeron, Luis Sojo, Karen Nelkenbrecher, Daniel P. Sutherlin, Amy Kim, Ivan William Hemeon, Andrea Lindgren, Jae H. Chang, Alla Yurevna Zenova, Shaoyi Sun, Jonathan Maher, Shannon D. Shields, Jun Li, Daniel F. Ortwine, David H. Hackos, Zhiwei Xie, Thilo Focken, Charles J. Cohen, Richard T. Dean, Shannon Decker, Janette Mezeyova, Kuldip Khakh, Antonio G. DiPasquale, Chien-An Chen, Andrew D. White, Brian Safina, Jodie Pang, Qi Jia, Sophia Lin, Jean-Christophe Andrez, J. P. Johnson, Steven J. McKerrall
Rok vydání: 2021
Předmět:
Zdroj: Journal of Medicinal Chemistry. 64:2953-2966
ISSN: 1520-4804
0022-2623
DOI: 10.1021/acs.jmedchem.1c00049
Popis: Nav1.7 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 Nav1.7 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 Nav1.7 inhibitors. Improvement of the metabolic stability by blocking the labile benzylic position led to the discovery of GDC-0310 (2), which possesses improved Nav selectivity and pharmacokinetic profile over 1.
Databáze: OpenAIRE
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