AMG-517 is a potent and selective TRPV1 antagonist, and antagonizes capsaicin, proton, and heat activation of TRPV1 with IC50 of 0.76 nM, 0.62 nM and 1.3 nM.
Vanilloid receptor-1 (TRPV1 or VR1), a well-characterized member of the transient receptor potential family of ion channels, has been implicated in the transmission of pain signaling[3]. AMG 517, a compound that potently blocks multiple modes of TRPV1 activation, shows potency in the capsaicin- and acid-mediated assays with IC50 values of 0.9 and 0.5 nM, respectively, while also processes excellent metabolic stability in human liver micosomes (CLin vitro < 5 μl/min/mg)[3]. In the capsaicin-induced hypothermia model in rats, AMG 517 was effective in a rodent on-target biochemical challenge model (capsaicin-induced flinch, ED50 = 0.33 mg/kg p.o.). In the complete Freund's adjuvant (CFA)-induced inflammatory pain model, AMG 517 showed dose-dependent inhibition of CFA-induced thermal hyperalgesia with efficacy at a minimum dose (MED) of 0.83 mg/kg (p.o.)[3].
作用机制
Hydrogen-bond donor−acceptor interactions between the carbonyl oxygen, NH proton, and the aromatic nitrogen of AMG 517 and the receptor are critical for its optimum potency.
搜索
