AMG 517 (AMG-517; AMG517) is a novel, potent and selective TRPV1 (vanilloid receptor-1) antagonist with potential anti-inflammatory activity. It antagonizes capsaicin, proton, and heat activation of TRPV1 with IC50 of 0.76 nM, 0.62 nM and 1.3 nM, respectively. The TRPV1 channel plays a suppressive role in the systemic inflammatory response syndrome (SIRS) by inhibiting production of tumor necrosis factor (TNF)α and possibly by other mechanisms. TRPV1 antagonists may decrease the resistance of older patients to infection and sepsis. When tested with stable CHO cell lines expressing TRPV1, treated with AMG-517 inhibited the activation of TRPV1.
理化性质和储存条件
| Molecular Weight (MW) | 430.4 |
|---|
| Formula | C20H13F3N4O2S |
|---|
| CAS No. | 659730-32-2 |
|---|
| Storage | -20℃ for 3 years in powder form |
|---|
| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO: 86 mg/mL (199.8 mM) |
|---|
| Water: <1 mg/mL |
| Ethanol: <1 mg/mL |
| Solubility (In vivo) | 10% Tween 80: 30 mg/mL |
|---|
| Synonyms | AMG-517; AMG 517; AMG517; BD-0082; BD 0082; BD0082 |
|---|
实验参考方法
| In Vitro | In vitro activity: AMG 517 inhibits CAP- (500 nM), acid- (pH 5.0), or heat-(45 °C) induced 45Ca2+ influx into human TRPV1-expressing CHO Cells with IC50 of 0.76 nM, 0.62 nM and 1.3 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 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. AMG 517 is a highly selective TRPV1 antagonist. The IC50 value for AMG 517 is>20 μM against 2-APB-activated TRPV2 and TRPV3, 4-αPDD-activated TRPV4, allyl isothiocyanate-activated TRPA1, and icilin-activated TRPM8 in cell-based assays that measure agonist-induced increases in intracellular calcium in CHO cells recombinantly expressing the appropriate TRP channel.
Kinase Assay: AMG 517 retains potency in the capsaicin- and acid-mediated assays with IC50 values of 0.9 and 0.5 nM.
Cell Assay: 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. |
|---|
| In Vivo | Oral administration of AMG 517 produces a dose-dependent increase in plasma concentrations, it also produces a dose-dependent decrease in the number of flinches induced by capsaicin treatment. The minimally effective dose (MED), based on a statistically significant difference in number of flinches from the vehicle versus capsaicin-administered group, is 0.3 mg/kg for AMG 517. The corresponding plasma concentrations are 90 to 100 ng/mL for AMG 517. AMG 517 (3 mg/kg) exhibits significant reductions in capsaicin-induced flinch up to 24 h after dosing. AMG 517 blocks thermal hyperalgesia in CFA model of pain. AMG 517 elicits hyperthermia in rodents, dogs and monkeys but not in TRPV1 knockout mice. Interestingly, hyperthermia evoked by TRPV1-selective antagonists is attenuated after repeated dosing of these antagonists to rats, dogs and monkeys, and TRPV1 knockout mice does not exhibit an impairment of thermoregulation. |
|---|
| Animal model | Male Sprague-Dawley rats |
|---|
| Formulation & Dosage | Dissolved in Ora-Plus-5% Tween 80; 0.003-3 mg/kg; oral gavage |
|---|
| References | J Pharmacol Exp Ther. 2007 Oct;323(1):128-37; Pain. 2008 May;136(1-2):202-10. |
|---|
m.cnreagent.com