Discovery of heterocyclic carbohydrazide derivatives as novel selective fatty acid amide hydrolase inhibitors: design, synthesis and anti-neuroinflammatory evaluation.

Discovery of heterocyclic carbohydrazide derivatives as novel selective fatty acid amide hydrolase inhibitors: design, synthesis and anti-neuroinflammatory evaluation.
Bioorg Med Chem Lett. 2020 Mar 19;:127118
Authors: Shang Y, Hao Q, Jiang K, He M, Wang J
Abstract
Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat pain, inflammation, and other central nervous system disorders. Herein, a series of novel heterocyclic carbohydrazide derivatives were firstly designed by the classic scaffold-hopping strategy. Then, multi-steps synthesis and human FAAH enzyme inhibiting activity assays were conducted. Among them, compound 26 showedstrong inhibition against human FAAH with IC50 of 2.8 μM. Corresponding docking studies revealed that the acyl hydrazide group of compound 26 well-occupied the acyl-chain binding pocket. It also exhibited high selectivity towards FAAH when comparing with CES2 and MAGL. Additionally, compound 26 effectively suppressed the LPS-induced neuroinflammation of microglial cells (BV2) via the reduction of interleukin-1β and tumor necrosis factor-α. Our results provided significative lead compounds for the further discovery of novel selective and safe FAAH inhibitors with potent anti-neuroinflammation activity.
PMID: 32216992 [PubMed - as supplied by publisher]

Source: Bioorganic and Medicinal Chemistry Letters - March 18, 2020 Category: Chemistry Authors: Shang Y, Hao Q, Jiang K, He M, Wang J Tags: Bioorg Med Chem Lett Source Type: research