[摘要]：High-throughput screening (HTS) identified benzothiazole analog (I) as a potent fatty acid amide hydrolase (FAAH) inhibitor. Structure-activity relationship (SAR) studies indicated that the sulfonyl group, the piperidine ring and benzothiazole were the key components to their activity, with II being the most potent analog in this series. Time-dependent preincubation study of compd. I was consistent with it being a reversible inhibitor. Activity-based protein-profiling (ABPP) evaluation of I in rat tissues revealed that it had exceptional selectivity and no off-target activity with respect to other serine hydrolases. Mol. shape overlay of I with a known FAAH inhibitor indicated that these compds. might act as transition-state analogs, forming putative hydrogen bonds with catalytic residues and mimicking the charge distribution of the tetrahedral transition state. The modeling study also indicated that hydrophobic interactions of the benzothiazole ring with the enzyme contributed to its extraordinary potency. These compds. may provide useful tools for the study of FAAH and the endocannabinoid system.
