化合物信息

Description

Cancer

Description

URB597 (KDS-4103) is a potent FAAH inhibitor with IC50 of 4.6 nM.

Targets

IC₅₀

In Vitro

URB597 binds in the hydrophobic pocket and catalytic core of FAAH that connects the active site residues to the membrane surface of FAAH. ^[1] URB597 inhibits FAAH activity in human liver microsomes with IC50 of 3 nM. ^[2] URB597 reduces the expression of the LPS-induced enzymes cyclo-oxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS; NOS2) in primary rat microglial cell, with a concomitant reduction in the release of the inflammatory mediators prostaglandin E2 (PGE2) and (NO) nitric oxide. ^[3] URB597 evokes Ca₂₊ entry in HEK293-F Cells transiently expressing human or rat TRPA1 gene. URB597 also activates Ca₂₊ entry in rat DRG neurons natively expressed TRPA1 channels. ^[4]

In Vivo

URB597 inhibits [³H]anandamide hydrolysis in rat brain membranes with a parallel increase in brain anandamide, OEA, and PEA content by inhibition of FAAH. URB597 enhances the hypothermia effect induced by ethanolamide by inhibiting FAAH. ^[5] When delivered intraperitonealy (0.3 mg/kg) URB597 reduces allodynia and hyperalgesia through cannabinoid CB1 and CB2 receptor-mediated analgesia in rats with inflammatory pain. ^[6] URB597 reduces the reduction in body weight gain and sucrose intake induced by the chronic mild stress in rats through inhibition of brain FAAH activity. ^[7] URB597 could reverse most depressive-like symptoms induced by adolescent THC exposure in femal rats. ^[8]

Clinical Trials

Features

Pharmacology

Membrane fractions are prepared from brain homogenates, and FAAH activity is assayed using [³H]anandamide (anandamide[ethanolamine-³H], 60 Ci/mmol) as a substrate. Rat brain membranes (50 μg protein) are incubated for 30 min at 37 °C in buffer containing [³H]anandamide and varying concentrations of URB597. At the end of the incubation period, we stopp the reactions with a mixture of chloroform/methanol and measured [³H]ethanolamine in the aqueous phase by liquid scintillation counting.

Animal Models

Adult male Wistar rats (250–300 g) and C57/BL6 or FAAH-/- mice

Formulation

sterile 0.9% sodium chloride solution

Doses

0.3 mg/kg

Administration

Inject subcutaneously in a single dose 2 hours or 16 hours before killing