Discovery of Acyl-sulfonamide Na_v1.7 Inhibitors GDC-0276 and GDC-0310

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.

Druggability of Voltage-Gated Sodium Channels—Exploring Old and New Drug Receptor Sites

“…Despite extensive research on developing aryl sulfonamide analogs as novel analgesics, only the compound PF-05089771 from Pfizer eventually entered phase II clinical trials for wisdom tooth removal, osteoarthritis of the knee, primary erythromelalgia, and painful diabetic peripheral neuropathy ( McDonnell et al, 2018 ). Genentech and Xenon Pharmaceuticals have two compounds (GDC-0276 and GDC-0310) that completed phase I clinical trials ( Rothenberg et al, 2019 ; Safina et al, 2021 ). Further clinical development of these compounds appears to be discontinued.…”

Towards Structure-Guided Development of Pain Therapeutics Targeting Voltage-Gated Sodium Channels

“…The Na V 1.7/Na V Ab—GX-936 structure complex, together with physiological characterizations of another sibling compound, GX-674 on Na V 1.7 VSD IV, revealed critical roles of R4 gating charge on S4 and YWxxV motif on S2 for potency and selectivity, respectively. Genentech in collaboration with Xenon Pharmaceuticals then advanced two highly potent acyl sulfonamide candidates targeting Na V 1.7, GDC-0276 (IC 50 = 0.4 nM) and GDC-0310 (IC 50 = 0.6 nM) for clinical developments ( Safina et al, 2021 ). GDC-0276has > 21 folds selectivity over hNa V 1.1, hNa V 1.2, hNa V 1.4, hNa V 1.5, hNa V 1.6 with the highest selectivity against hNa V 1.6 ( ∼ 1,200 fold) and the lowest selectivity against hNa V 1.4 ( ∼ 21 fold).…”

“…GDC-0276has > 21 folds selectivity over hNa V 1.1, hNa V 1.2, hNa V 1.4, hNa V 1.5, hNa V 1.6 with the highest selectivity against hNa V 1.6 ( ∼ 1,200 fold) and the lowest selectivity against hNa V 1.4 ( ∼ 21 fold). GDC-0310has > 63 fold selectivity over hNa V 1.1, hNa V 1.2, hNa V 1.5, ∼ 330 fold over Na V 1.6 but only a modest ∼ 6 folds selectivity over hNa V 1.4 ( Safina et al, 2021 ). Xenon Pharmaceuticals and Genentech have stopped the development of GDC-0276 and GDC-0310 after Phase I trials for non-disclosed reasons.…”

Inhibition of NaV1.7: the possibility of ideal analgesics

“…In their article, they mentioned that 82-fold target coverage was required for robust efficacy in a transgenic mouse model expressing human Na V 1.7 with an IEM mutation (I848T, IEM transgenic mouse). 77,78 The clinical efficacy of PF-05089771 is discussed in the following section.…”