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  • Trifluoromethyl ketones and fluorophosphates were

    2021-09-09

    Trifluoromethyl ketones and fluorophosphates were the first generation FAAH inhibitors identified. They showed good in vitro FAAH inhibition potency, but most of them exhibited poor selectivity for FAAH over other serine hydrolases (such as the triacylglycerol hydrolase and the membrane-associated hydrolase KIAA1363)., , , Over the past decade, research on FAAH inhibitors has been significantly developed. Numerous selective FAAH inhibitors have been identified. Generally, according to the different interaction mechanisms, FAAH inhibitors can be classified as covalent reversible inhibitors, such as OL-135, (), covalent irreversible inhibitors, such as URB597, (), or non-covalent reversible inhibitors, such as compound disclosed by Abbott () and compound synthesized by Amgen (). OL-135, an α-ketoheterocycle, has been discovered in 2004 as a covalent, selective, and reversible FAAH inhibitor with an IC of 2nM. Especially, its carbonyl group has been demonstrated to interact with the Ser241 of the catalytic triad accompanied by the formation of an enzyme–substrate tetrahedral intermediate. Additionally, the pyridine group of OL-135 has been identified to form H-bonds with the Lys142 and the Thr236, which is favorable for the interaction between OL-135 and FAAH., URB597, a representative carbamate-based selective FAAH inhibitor, was identified to irreversible bind to FAAH accompanied by the generation of a carbamylated-enzyme adduct. To date, URB597 is considered as one of the most potent FAAH inhibitors with an IC of 4.6nM., As previously reported by our research group, 3-carboxamido-5-arylisoxazole has been regarded as an interesting scaffold for developing FAAH inhibitors., Typically, compound (IC=88nM, ) displayed a potent FAAH inhibitory capacity in vitro and produced protective efficacy on a 2,4,6-trinitrobenzene sulfonic Linezolid (TNBS)-induced colitis mouse model., Recently, different pharmacomodulations were carried out on this series. The replacement of the benzodioxol ethyl group appended to the carboxamide function by an adamant-1-yl group and the substitution of the terminal phenyl ring by a pentoxy group led to a substantial increase of FAAH inhibitory efficacy (, IC=8nM, ). Compound produced anti-inflammatory effect in a dextran sulfate sodium (DSS)-induced acute colitis model in mice. In this context, a novel series of compounds based on this interesting scaffold was designed. The replacement of the phenyl moiety of compound by a pyridine group or the introduction of different aromatic substituents instead of the pentoxy group at the position of the phenyl ring is supposed to optimize physicochemical parameters (such as Log). The target compounds were obtained in five steps. The Claisen condensation of aromatic ketones and with diethyl oxalate in the presence of sodium ethanolate afforded β-diketoesters (47%) and (39%), respectively. It has been demonstrated that these β-diketoesters are in their enol form, which is probably due to the formation of an internal hydrogen bond., , Then, cyclization reaction was performed to convert compounds and into 5-aryl isoxazole-3-carboxylates (78%) and (71%) by addition of hydroxylamine hydrochloride in ethanol at reflux. Furthermore, saponification into 5-aryl isoxazole-3-carboxylate carboxylic acids (98%) and (95%) was carried out, followed by amidification with 1-adamantanamine hydrochloride to achieve to precursor compounds (67%) and (53%). Finally, a tetrakis (triphenylphosphine)palladium(0)-catalyzed Suzuki reaction with different aromatic Linezolid boronic acids or boronic acid pinacol esters afforded -(adamantan-1-yl)-5-aryl isoxazole-3-carboxamide derivatives – with good yields (76–89%) (). The -(adamantan-1-yl)-5-aryl isoxazole-3-carboxamides – and reference compounds ( and URB597) were assessed for their ability to inhibit the hydrolysis of 7-amino-4-methyl coumarin-arachidonamide (AMC-AA), a fluorescent FAAH substrate, by human recombinant FAAH (expressed in SF21 cells) after a 15min preincubation with 4 U/mL of enzyme at 37°C in Tris buffer pH 9. All the compounds were firstly screened at the concentration of 10μM. The half maximal inhibitory concentrations (IC) were determined for compounds exhibiting a specific inhibition superior to 50% for FAAH.