JNJ 1661010

JNJ-1661010是一种有效的，选择性的FAAH抑制剂，IC50分别为10 nM(大鼠)和12 nM (人类)，作用于FAAH-1比作用于FAAH-2选择性高100倍以上。 FAAH preincubated with JNJ-1661010 suggests a slow reversibility of the interaction between the JNJ-1661010 and the active site, which is accelerated at higher temperatures. JNJ-1661010 is a covalent, mechanism-based substrate inhibitor as examined by LC-ESI-MS. JNJ-1661010 docks with the phenylthiadiazole in the hydrophobic tunnel and the phenylurea in the hydrophilic pocket of FAAH. JNJ-1661010 (20 mg/kg i.p.) inhibits FAAH by at least 85% for up to 4 h after dosing, resulting accumulation of lipid ethanolamides in rat brain. JNJ-1661010 dose-dependently reverses the tactile allodynia with a maximum efficacy of approximately 90% at 30 min postdose in both Mild Thermal Injury (MTI) mice and rat model. JNJ-1661010 (20 mg/kg) reverses tactile allodynia by 60.8% at 30 min in rat spinal nerve ligation injury model. JNJ-1661010 (50 mg/kg i.p.) shows a significant attenuation of the hyperalgesia at 30 min postdose in rat carrageenan model of inflammatory pain. Rats dosed with JNJ-1661010 (20 mg/kg i.p.) has a plasma Cmax of 26.9 μM at the Tmax of 0.75 h and a Cmax in the brain of 6.04 μM at the Tmax of 2 h. JNJ-1661010 (20 mg/kg i.p.) inhibits brain FAAH and elevates AEA level in brain tissue in rat. JNJ-1661010 (Takeda-25)是一种有效的，选择性的FAAH抑制剂，IC50分别为10 nM(大鼠)和12 nM (人类)，作用于FAAH-1比作用于FAAH-2选择性高100倍以上。

Target	Value
FAAH (rat)	10 nM
FAAH (human)	12 nM

FAAH与JNJ-1661010预培养表明，JNJ-1661010和活性部位相互作用具有缓慢可逆性，并且在高温下会加速。 LC-ESI-MS检测表明，JNJ-1661010是一种共价的，基于机制的底物抑制剂。JNJ-1661010与苯基噻二唑在疏水性通道中对接，与苯脲在FAAH的亲水性口袋中对接。

JNJ-1661010(20 mg/kg i.p.)至少抑制85%的FAAH，给药后作用能维持4小时以上，导致大鼠大脑中脂质乙醇酰胺积累。温和热损伤的(MTI)小鼠和大鼠模型中，JNJ-1661010剂量依赖性逆转触觉异常疼痛，最大效能在给药30分钟后大约为90%。在大鼠脊髓神经结扎损伤模型中，JNJ-1661010 (20 mg/kg)给药30分钟时逆转60.8%触觉异常疼痛。在大鼠角叉菜胶炎性疼痛模型中，JNJ-1661010 (50 mg/kg i.p.)给药30分钟后显著减弱痛觉过敏。大鼠以JNJ-1661010 (20 mg/kg i.p.)给药，Tmax为0.75 h时，血浆Cmax为26.9 μM，Tmax为2 h时，大脑中Cmax为6.04 μM。JNJ-1661010 (20 mg/kg i.p.)抑制大鼠大脑中FAAH，并提高脑组织中AEA水平。