1. Discovery of Acyl-sulfonamide Na v 1.7 Inhibitors GDC-0276 and GDC-0310.
- Author
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Safina BS, McKerrall SJ, Sun S, Chen CA, Chowdhury S, Jia Q, Li J, Zenova AY, Andrez JC, Bankar G, Bergeron P, Chang JH, Chang E, Chen J, Dean R, Decker SM, DiPasquale A, Focken T, Hemeon I, Khakh K, Kim A, Kwan R, Lindgren A, Lin S, Maher J, Mezeyova J, Misner D, Nelkenbrecher K, Pang J, Reese R, Shields SD, Sojo L, Sheng T, Verschoof H, Waldbrook M, Wilson MS, Xie Z, Young C, Zabka TS, Hackos DH, Ortwine DF, White AD, Johnson JP Jr, Robinette CL, Dehnhardt CM, Cohen CJ, and Sutherlin DP
- Subjects
- Animals, Azetidines chemistry, Azetidines pharmacokinetics, Benzamides chemistry, Benzamides pharmacokinetics, Cells, Cultured, HEK293 Cells, Humans, Piperidines chemistry, Piperidines pharmacokinetics, Piperidines pharmacology, Rats, Sprague-Dawley, Sulfonamides chemistry, Sulfonamides pharmacokinetics, Voltage-Gated Sodium Channel Blockers chemistry, Voltage-Gated Sodium Channel Blockers pharmacokinetics, Rats, Azetidines pharmacology, Benzamides pharmacology, Drug Discovery, NAV1.7 Voltage-Gated Sodium Channel metabolism, Sulfonamides pharmacology, Voltage-Gated Sodium Channel Blockers pharmacology
- Abstract
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 Nav 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 Nav 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 Nav selectivity and pharmacokinetic profile over 1 .- Published
- 2021
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