AM-2099 is a voltage-gated sodium channel Nav1.7 inhibitor (IC50: 0.16 μM).

Nav1.7 (human):0.16 μM, Nav1.7 (mouse):0.18 μM, Nav1.7 (rat):3.5 μM

AM-2099 exhibits over 100-fold selectivity for the Nav1.7 channel compared to Nav1.3, Nav1.4, Nav1.5, and Nav1.8, with diminished selectivity observed for Nav1.1, Nav1.2, and Nav1.6. Its affinity for the hERG channel is low (>30 μM), and it lacks significant inhibition (>50%) against both a 100-kinase panel (1 μM) and a broad CEREP panel (10 μM)[1]. In heterologous cells, AM-2099 consistently inhibits NaV1.7 in human, mouse, dog, and cynomolgus monkey, showing decreased efficacy against rat NaV1.7.

AM-2099 exhibits a dose-dependent escalation in plasma exposure accompanied by a simultaneous dose-dependent decrease in scratching bouts in comparison to vehicle-treated animals, notably achieving statistical significance at the 60 mg/kg dosage[1]. It also presents a favorable pharmacokinetic profile in both rats and dogs. In rats, AM-2099 is characterized by low total clearance, moderate volume of distribution at steady state (Vdss), and half-life. Conversely, in dogs, it features very low clearance, a low Vdss, and an extended half-life (18 h).