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

Affiliation

Safina BS(1), McKerrall SJ(1), Sun S(2), Chen CA(3), Chowdhury S(2), Jia Q(2), Li J(1), Zenova AY(2), Andrez JC(2), Bankar G(2), Bergeron P(1), Chang JH(1), Chang E(2), Chen J(1), Dean R(2), Decker SM(2), DiPasquale A(1), Focken T(2), Hemeon I(2), Khakh K(2), Kim A(1), Kwan R(2), Lindgren A(2), Lin S(2), Maher J(1), Mezeyova J(2), Misner D(1), Nelkenbrecher K(2), Pang J(1), Reese R(1), Shields SD(1), Sojo L(2), Sheng T(2), Verschoof H(2), Waldbrook M(2), Wilson MS(2), Xie Z(2), Young C(2), Zabka TS(1), Hackos DH(1), Ortwine DF(1), White AD(3), Johnson JP Jr(2), Robinette CL(2), Dehnhardt CM(2), Cohen CJ(2), Sutherlin DP(1).
Author information:
(1)Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
(2)Xenon Pharmaceuticals, Inc., 200-3650 Gilmore Way, Burnaby, British Columbia V5G 4W8, Canada.
(3)Chempartner, Building No. 5, 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, P.R. China.

Abstract

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.