GDC-0276

GDC-0276 is a potent, selective, reversible, orally active voltage-gated sodium channel 1.7 (Na_V1.7) inhibitor with an IC₅₀ value of 0.4nM^[1]. Na_V1.7 is a complex protein with multiple druggable sites that plays a vital role in the transmission of pain signals^[2]. GDC-0276 is a class of acylsulfonamide Na_V1.7 inhibitors with good tolerability and good pharmacokinetic properties^{[3, 4]}. GDC-0276 can be used to treat pain and address the shortcomings of existing analgesics, such as addiction and off-target side effects^[5].

References:
[1] Nguyen P T, Yarov-Yarovoy V. Towards structure-guided development of pain therapeutics targeting voltage-gated sodium channels[J]. Frontiers in pharmacology, 2022, 13: 842032.
[2] McKerrall S J, Sutherlin D P. Nav1. 7 inhibitors for the treatment of chronic pain[J]. Bioorganic & medicinal chemistry letters, 2018, 28(19): 3141-3149.
[3] Rothenberg M E, Tagen M, Chang J H, et al. Safety, tolerability, and pharmacokinetics of GDC-0276, a novel Na V 1.7 inhibitor, in a first-in-human, single-and multiple-dose study in healthy volunteers[J]. Clinical drug investigation, 2019, 39: 873-887.
[4] Safina B S, McKerrall S J, Sun S, et al. Discovery of acyl-sulfonamide NaV1. 7 inhibitors GDC-0276 and GDC-0310[J]. Journal of medicinal chemistry, 2021, 64(6): 2953-2966.
[5] Stumpf A, Cheng Z K, Beaudry D, et al. Improved synthesis of the Nav1. 7 inhibitor GDC-0276 via a highly regioselective SNAr reaction[J]. Organic Process Research & Development, 2019, 23(9): 1829-1840.

GDC-0276是一种有效的、选择性的、可逆的具口服活性的电压门控型钠离子通道1.7（Na_V1.7）抑制剂，IC₅₀值为0.4nM^[1]。Na_V1.7是一种具有多个成药位点的复杂蛋白质，在疼痛信号的传递中起着至关重要的作用^[2]。GDC-0276是一类酰基磺酰胺Na_V1.7抑制剂，耐受性良好，具有良好的药代动力学特征^{[3, 4]}。GDC-0276能够用于治疗疼痛以及解决现有止痛药物缺陷，如成瘾和脱靶副作用的相关研究^[5]。