Synthesis and Evaluation of Benzothiazole-Based Analogues as Novel, Potent, and Selective Fatty Acid Amide Hydrolase Inhibitors

Abstract

High-throughput screening (HTS) identified benzothiazole analogue 3 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 16j being the most potent analogue in this series. Time-dependent preincubation study of compound 3 was consistent with it being a reversible inhibitor. Activity-based protein-profiling (ABPP) evaluation of 3 in rat tissues revealed that it had exceptional selectivity and no off-target activity with respect to other serine hydrolases. Molecular shape overlay of 3 with a known FAAH inhibitor indicated that these compounds might act as transition-state analogues, 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 compounds may provide useful tools for the study of FAAH and the endocannabinoid system.

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

“…117 The determination of selectivity by ABPP indicated that compound 87 exerted no off-target activity against numerous enzymes (such as TGH, KIAA1363, and carboxy esterases). 117 A series of non-covalent and reversible FAAH inhibitors was disclosed by Amgen in 2011. 118 Typically, compound 88 ( Figure 36) exerted potent capacity to disable FAAH-mediated hydrolysis.…”

Preclinical Characterization of the FAAH Inhibitor JNJ-42165279

“…30 Urea derivatives as prepared by Pfizer, Takeda, and us operate via a similar mechanism but have aromatic amines as leaving groups rather than alcohols or phenols. 31 40 Amgen, 41 Renovis, 42 and Johnson and Johnson. 43 Several compounds have been profiled to some degree in the clinic.…”

Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields

“…Inhibition by N-alkylcarbamates is based on irreversible acylation of the active site serine [25]. Recently reported other structure families with inhibitory activity against FAAH include (thio)hydantoins [26], piperidine-and piperazine ureas [27,28], sulfonyl derivatives [29] and boronic acid derivatives [30].…”