A series of derivatives of 1-(4-octylphenoxy)-3-(2H-tetrazol-2-yl)propan-2-one (3) and 1-(4-octylphenoxy)-3-(1H-tetrazol-1-yl)propan-2-one (4) was synthesized and tested for fatty acid amide hydrolase (FAAH) inhibitory potency and phase I metabolic stability. Introduction of certain substituents like 4-chlorophenyl, 4-methoxycarbonylphenyl and carboxyl in position 5 of the tetrazole ring of 3 led to a significant increase of the metabolic stability of the scissile ketone pharmacophore, while the high activity towards FAAH was not affected markedly. In contrast, substituents in position 5 of the heterocyclic system of 4 did not have a considerable impact on the undesired ketone reduction. Furthermore, the effect of shielding the ketone group of some derivatives of 3 by a methyl substituent in position 3 of the propan-2-one scaffold and the consequences of the replacement of the lipophilic octyl residue of these compounds by more drug-like substituents were examined.
Keywords: Covalent reversible inhibitors; Fatty acid amide hydrolase; Metabolic stability; Propan-2-one.
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