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。

一般步骤：在25 mL圆底烧瓶中加入1-(3-苯基-1,2,4-噻二唑-5-基)哌嗪（1.00 g，4.06 mmol）和三乙胺（0.565 mL，4.06 mmol）的四氢呋喃（20 mL）溶液。将反应混合物置于冰浴中冷却至0°C，随后缓慢滴加异氰酸苯酯（0.529 mL，4.87 mmol）。滴加完毕后，移除冰浴，将反应混合物在室温下搅拌3小时。反应完成后，向混合物中加入二异丙醚（40 mL）以沉淀产物。通过过滤收集固体，并用己烷和乙酸乙酯的混合溶剂（体积比1:1）进行重结晶，得到N-苯基-4-(3-苯基-1,2,4-噻二唑-5-基)哌嗪-1-甲酰胺1.19 g，收率80.4%，为白色固体。产物结构经1H-NMR（CDCl3）确认：δ 3.70（8H，s），6.43（1H，s），7.06-7.11（1H，m），7.29-7.46（7H，m），8.17-8.21（2H，m）。

参考文献：

[1] Patent: EP1813606, 2007, A1. Location in patent: Page/Page column 32-33

[2] Patent: US2007/4741, 2007, A1. Location in patent: Page/Page column 14

[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 17, p. 4838 - 4843