GNE-616 是一种高效的，代谢稳定的，口服生物可利用的，亚型选择性的 Nav1.7 抑制剂 (对 hNav1.7 的 Ki 值为 0.79 nM，Kd 值为 0.38 nM)，用于治疗慢性疼痛。 与 hNav1.1，hNav1.3, hNav1.4，hNav1.5 相比，GNE-616 显示大于 1000 nM 的 Kd 值和大于 2500 倍的选择性。对 hNav1.2 和 hNav1.6 的选择性分别是 31 倍和 73 倍。
CAS：2349371-81-7
分子式：C24H23F4N5O3S
分子量：537.53
纯度：98%
存储：Store at -20°C

Background:

GNE-616 is a highly potent, metabolically stable, orally bioavailable, and subtype selective Nav1.7 inhibitor (Ki of 0.79 nM and Kd of 0.38 nM for hNav1.7) for the treatment of chronic pain. GNE-616 shows >1000 nM Kd and >2500-fold selectivity over hNav1.1, hNav1.3, hNav1.4, and hNav1.5. Selectivity over hNav1.2 and hNav1.6 is more modest at 31- and 73-fold, respectively[1]. Ki: 0.79 nM (hNav1.7)[1]Kd: 0.38 nM (hNav1.7), 12 nM (hNav1.2), 29 nM (hNav1.6)[1]

Site-directed mutagenesis is critical for the isoform selectivity profile of GNE-616 (hNav1.7, Kd: Y1537s/W1538=170±67 nM, V1541=3.9±1.1 nM, Y1537s/W1538/V1541=790±350 nM)[1].

GNE-616 shows robust activity in a Nav1.7-dependent inherited erythromelalgia (IEM) PK/PD model with an EC50 of 740 nM and EC50,u of 9.6 nM[1].

[1]. McKerrall SJ, et al. Structure- and Ligand-Based Discovery of Chromane Arylsulfonamide Nav1.7 Inhibitors for the Treatment of Chronic Pain. J Med Chem. 2019 Apr 25;62(8):4091-4109.