ω‐Imidazolyl‐ and ω‐Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability

Abstract

Fatty acid amide hydrolase (FAAH) is a serine hydrolase that terminates the analgesic and anti-inflammatory effects of endocannabinoids such as anandamide. Herein, structure-activity relationship studies on a new series of aryl N-(ω-imidazolyl- and ω-tetrazolylalkyl)carbamate inhibitors of FAAH were investigated. As one result, a pronounced increase in inhibitory potency was observed if a phenyl residue attached to the carbamate oxygen atom was replaced by a pyridin-3-yl moiety. The most active compounds exhibited IC50 values in the low nanomolar range. In addition, investigations on the metabolic properties of these inhibitors were performed. In rat liver homogenate and in porcine plasma, the extent of their degradation was shown to be strongly dependent on the kind of aryl residue bound to the carbamate as well as on the length and type of the alkyl spacer connecting the carbamate group with the heterocyclic system. With the aid of esterase inhibitors it was shown that in porcine plasma, carboxylesterase-like enzymes and paraoxonase are involved in carbamate cleavage. Moreover, it was found that highly active pyridin-3-yl carbamates reacted with albumin, which led to covalent albumin adducts.

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

“…81 Most recently, Lehr and co-workers disclosed a novel series of ω-imidazolyl and ω-tetrazolyl alkyl carbamates as potent FAAH inhibitors. 82 Although compound 43 (IC50 = 5.3 nM, Figure 19) manifested optimal potency against FAAH at single-digit nanomolar concentrations, its instability in plasma made it a poor candidate for systemic administration. Compounds 44 and 45 (IC50 = 11 and 81 nM, respectively, Figure 19) exerted potent FAAH inhibition in the two-digit nanomolar range.…”

Solvatochromism of N-aryl-phenylacetamides

“…Derivati amida imaju veoma širok spektar primene i pokazuju različite tipove bioloških aktivnosti. Imaju antimikrobiološko i antibakterijsko dejstvo [1], koriste se kao lekovi protiv artritisa i kao antidepresivi [2], a imaju veliku primenu i kao antiinflamantorna i analgetička sredstva [3]. Takođe, predstavljeni su kao potencijalni lekovi u borbi protiv tumora [4].…”

(Indolylalkyl)piperidine carbamates as inhibitors of fatty acid amide hydrolase (FAAH)

“…This significant instability of 8 was due to hydrolysis by plasma paraoxonase and bisIJpnitrophenyl)phosphate-sensitive carboxylesterases as proven with inhibitors of these enzymes. 30 In contrast, all new piperidine carbamates displayed a pronounced stability in porcine blood plasma.…”

“…The derivatives of 17 with varying substituents at the phenyl ring of the indole scaffold (26)(27)(28)(29)(30)(31)(32)(33)(34) and the azaindole compounds 39-42 were synthesized by reaction of 16 with the appropriate indole employing conditions similar to those described for the preparation of 17.…”

“…25 The metabolic stability in rat liver S9 fractions and in porcine blood plasma was evaluated with reversed phase HPLC and MS-detection. 30 Investigations on the change of inhibitory potency of the phenyl N-indolylalkylcarbamates 5-9 in dependence of the length of the alkyl chain exhibited two maxima of activity. 21 With IC 50 values of about 0.1 μM each, the compounds with pentyl and heptyl residues (6 and 8) possessed the highest inhibitory activities in this series of compounds (Table 1).…”