| Bioactivity | AMG 517 is a potent and selective vanilloid receptor-1 (TRPV1) antagonist with an IC50 of 0.5 nM. | ||||||||||||
| Target | IC50: 0.5 nM (TRPV1) | ||||||||||||
| Invitro | 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]. | ||||||||||||
| Name | AMG 517 | ||||||||||||
| CAS | 659730-32-2 | ||||||||||||
| Formula | C20H13F3N4O2S | ||||||||||||
| Molar Mass | 430.40 | ||||||||||||
| Appearance | Solid | ||||||||||||
| Transport | Room temperature in continental US; may vary elsewhere. | ||||||||||||
| Storage |
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| Reference | [1]. Doherty EM, et al. Novel vanilloid receptor-1 antagonists: 2. Structure-activity relationships of 4-oxopyrimidines leading to the selection of a clinical candidate. J Med Chem. 2007 Jul 26;50(15):3515-27. [2]. Gavva NR, et al. Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade. J Pharmacol Exp Ther. 2007 Oct;323(1):128-37. |