AMG-517

Names

[ Name ]:
AMG-517

[Synonym ]:
BD-0082
N-(4-(6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide
UNII-172V4FBZ75
N-[4-({6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide
Acetamide, N-[4-[[6-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl]oxy]-2-benzothiazolyl]-
N-[4-({6-[4-(Trifluoromethyl)phenyl]-4-pyrimidinyl}oxy)-1,3-benzothiazol-2-yl]acetamide
N-[4-[[6-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl]oxy]-2-benzothiazolyl]-acetamide
AMG-517
N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide
N-(4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamide
AMG517
AMG 517

Biological Activity

[Description]:

AMG 517 is a potent and selective vanilloid receptor-1 (TRPV1) antagonist with an IC50 of 0.5 nM.

[Related Catalog]:

Signaling Pathways >> Membrane Transporter/Ion Channel >> TRP Channel

Research Areas >> Neurological Disease

[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].

[Animal admin]

Rats: After multiple days of full habituation to the testing equipment and paradigm, CFA-induced thermal hyperalgesia is evaluated by measuring paw withdrawal latencies in male Sprague-Dawley rats. Twenty-one hours after CFA injection (50 μL of 0.1%), animals are dosed (p.o.) with AMG 517 or AMG8163 at a dose range of 0.001 to 30 mg/kg in a volume of 5 mL/kg. Two hours after drug dosing (23 h after CFA injection), paw withdrawal latencies are measured using modified Hargreaves hot boxes by investigators fully blinded to treatment conditions[2].

[References]

[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.

[Related Small Molecules]

capsaicin | Capsazepine | EIPA | Diphenyleneiodonium chloride | HC-030031 | SKF-96365 | HC 067047 | AMG 9810 | GSK-1016790A | SAR7334 | PF-4840154 | RN-1734 | SB-366791 | IcilinAG-3-5 | ML204

Chemical & Physical Properties

[ Density]:
1.5±0.1 g/cm3

[ Melting Point ]:
227ºC

[ Molecular Formula ]:
C₂₀H₁₃F₃N₄O₂S

[ Molecular Weight ]:
430.403

[ Exact Mass ]:
430.071136

[ PSA ]:
108.73000

[ LogP ]:
5.41

[ Index of Refraction ]:
1.645

[ Storage condition ]:
-20℃

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Related Compounds

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