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[摘要]：Toll-like receptor 4 (TLR4), a membrane-spanning receptor protein that functions in complex with its accessory protein MD-2, is an intriguing target for therapeutic development. Herein, we report the identification of a series of novel TLR4 inhibitors and the development of a robust, enantioselective synthesis using an unprecedented Mannich type reaction to functionalize a pyrazole ring. In silico and cellular assay results demonstrated that compound 1 and its analogues selectively block TLR4 activation in live cells. Animal model tests showed that 1 and its derivatives could potentiate morphine-induced analgesia in vivo, presumably by attenuating the opioid-induced TLR4 activation. |
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