AMG 517

AMG 517 is a potent and selective vanilloid receptor-1 (TRPV1) antagonist with an IC₅₀ of 0.5 nM. IC50 & Target: IC50: 0.5 nM (TRPV1)^[1] In Vitro: AMG 517 retains potency in the capsaicin- and acid-mediated assays with IC₅₀ values of 0.9 and 0.5 nM^[1]. AMG 517 inhibits capsaicin, pH 5, and heat-induced⁴⁵Ca²⁺ uptake into cells expressing TRPV1 with IC₅₀ values of 1 to 2 nM. AMG 517 blocks capsaicin-, proton-, and heat-induced inward currents in TRPV1-expressing cells similarly. AMG 517 inhibits native TRPV1 activation by capsaicin in rat dorsal root ganglion neurons with an IC50 value of 0.68 ± 0.2 nM. AMG 517 is a competitive antagonist of both rat and human TRPV1 with dissociation constant (Kb) values of 4.2 and 6.2 nM, respectively^[2]. In Vivo: AMG 517 is shown to be effective in a rodent “on-target” biochemical challenge model (capsaicin-induced flinch, ED₅₀=0.33 mg/kg p.o.) and is antihyperalgesic in a model of inflammatory pain (CFA-induced thermal hyperalgesia, MED=0.83 mg/kg, p.o.)^[1].The minimally effective dose is 0.3 mg/kg for AMG 517 and the corresponding plasma concentration is 90 ng/mL. Oral administration of AMG 517 reverses established thermal hyperalgesia in a dose-dependent manner at 21 h after CFA injection. AMG 517 causes transient hyperthermia in rodents, dogs, and monkeys. AMG 517 induces hyperthermia in a steep dose-dependent manner, with 0.3, 1, and 3 mg/kg associated with 0.5, 0.6, and 1.6°C increases in body temperature, respectively. Body temperatures of rats treated with all doses of AMG 517 return to baseline within 10 to 20 h^[2].