Exceptionally potent inhibitors of fatty acid amide hydrolase: The enzyme responsible for degradation of endogenous oleamide and anandamide

Abstract

The development of exceptionally potent inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid), and anandamide (an endogenous ligand for cannabinoid receptors) is detailed. The inhibitors may serve as useful tools to clarify the role of endogenous oleamide and anandamide and may prove to be useful therapeutic agents for the treatment of sleep disorders or pain. The combination of several features-an optimal C12-C8 chain length, -unsaturation introduction at the corresponding arachidonoyl ⌬ 8,9 ͞⌬ 11,12 and oleoyl ⌬ 9,10 location, and an ␣-keto N4 oxazolopyridine with incorporation of a second weakly basic nitrogen provided FAAH inhibitors with Kis that drop below 200 pM and are 10 2 -10 3 times more potent than the corresponding trifluoromethyl ketones.

The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors

“…4a and b). Inhibition of FAAH by URB597 (4) was shown to be irreversible and by 1-(oxazolo [4,5-b]pyridin-2-yl)-1-oxo-dodecane (CAY10435) [18] inhibition was reversible (Fig. 4a), as has been described in the Enzyme activity was measured at the indicated time-points after 500-fold dilution of the enzyme-inhibitor complex.…”

“…The differences in the FAAH and MGL inhibition potencies among the other dihydrothiazoline derivatives with different N-alkyl groups (14)(15)(16)(17)(18)(19)(20) were mainly not notable. However, with cycloalkyl and benzylic groups (14)(15)(16)(17)(18)(19) complete MGL inhibition was not observed, even at the highest concentrations tested (1 mM).…”

“…However, with cycloalkyl and benzylic groups (14)(15)(16)(17)(18)(19) complete MGL inhibition was not observed, even at the highest concentrations tested (1 mM). This remaining enzyme activity can be explained by an additional enzyme activity distinct from MGL or by low aqueous solubility of these compounds.…”

“…Therefore, several FAAH inhibitors have been developed (see for review Ref. [12]), including various fatty acid derivatives [13][14][15][16][17], and non-lipid inhibitors such as a-keto heterocycles [18][19][20], carbamate derivatives [21][22][23][24][25], (thio)-hydantoins [26] and most recently, selective piperidine/piperazine ureas [27,28]. Probably, the most well-studied FAAH inhibitors are the carbamate-based 3 0 -carbamoylbiphenyl-3-yl ester (4, URB597) ( Fig.…”

Correlation of inhibitor effects on enzyme activity and thermal stability for the integral membrane protein fatty acid amide hydrolase

“…In a more high throughput manner and with an increased array of inhibitors, we report a survey of a representative library of reversible inhibitors that has been created based on the enzyme's natural substrates. 10 To date, these compounds have been ranked as inhibitors based primarily on K i . [11][12][13][14][15] We explore the relationship between K i and stability, and the potential use of protein melting point as a complimentary metric for assessing ligand efficacy for crystallization and drug candidate screening.…”