AM-2099 is a potent and selective inhibitor of voltage-gated sodium channel Nav1.7 with an IC50 of 0.16 μM for human Nav1.7.
In heterologous cells, comparable inhibition is observed across human, mouse, dog, and cynomolgus monkey NaV1.7 with reduced activity against rat NaV1.7. AM-2099 is more than 100-fold selective over Nav1.3, Nav1.4, Nav1.5, and Nav1.8, while lower levels of selectivity are observed against Nav1.1, Nav1.2, and Nav1.6. AM-2099 demonstrates low affinity for hERG (>30 µM) and does not show greater than 50% inhibition against a panel of 100 kinases (1 µM) and a broad CEREP panel (10 µM). [1].
AM-2099 demonstrates a favorable pharmacokinetic profile in rat and dog. In rats AM-2099 shows low total clearance and moderate Vdss and half-life. In contrast, when dosed in dogs AM-2099 shows very low clearance, a low Vdss and long halflife (18 h). AM-2099 demonstrates a dose-dependent increase in plasma exposure with a concomitant dose-dependent reduction in scratching bouts compared to vehicle-treated animals, with a statistically significant reduction observed at the 60 mg/kg dose[1].
[1]. Marx IE, et al. Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement. ACS Med Chem Lett. 2016 Sep 21;7(12):1062-1067.