Development of indole-2-carbonyl piperazine urea derivatives as selective FAAH inhibitors for efficient treatment of depression and pain.

[Display omitted] • A series of novel indole-2-carbonyl piperazine urea derivatives were discovered as FAAH inhibitors. • Active compound 4i showed potent FAAH activities (IC 50 = 0.12 μM) and high selectivity over CB receptors, CES2, ABHD6 and MAGL. • Compound 4i exhibited an adequate pharmacokinetics profile in rodents and superior metabolic stability in human liver microsome. • Compound 4i effectively ameliorated reserpine-induced depression-like behaviors and also exhibited remarkable analgesic activity in vivo test. Fatty acid amide hydrolase (FAAH), a serine hydrolase with significant role in the hydrolysis of endocannabinoids, is a promising therapeutic target for peripheral and central nervous system related disorders, including pain, neuroinflammation and depression. Employing a structure-based approach, a novel series of indole-2-carbonyl piperazine urea derivatives were designed and synthesized as FAAH inhibitors for the treatment of pain-depression comorbidity. Among them, compound 4i emerged as the most potent inhibitor (IC 50 = 0.12 μM) with fine selectivity versus CES2, ABHD6, MAGL and the cannabinoid receptor, which also displayed superior metabolic stability in human liver microsome and an adequate pharmacokinetic profile in rodents. Treatment of depressed rats with 4i demonstrated favorable antidepressant-like effects not only by increasing the level of BDNF in the hippocampus but also by restraining the apoptosis of hippocampal neurons. Also, 4i effectively suppressed the LPS-induced neuroinflammation in vitro. Moreover, 4i exhibited potent analgesic activity, which indicated its promising therapeutical application for pain and depression. These meaningful results shed light on FAAH inhibitors as promising pain-depression comorbidity therapeutics. [ABSTRACT FROM AUTHOR]