Discovery of a Potent, Selective, and Efficacious Class of Reversible α-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Effective as Analgesics

Boger, Dale L.; Miyauchi, Hiroshi; Du, Wu; Hardouin, Christophe; Fecik, Robert; Cheng, Huilin; Hwang, Inkyu; Hedrick, Michael; Leung, Debbie; Acevedo, Orlando; Guimarães, Cristiano Ruch Werneck; Jorgensen, William L.; Cravatt, Benjamin F.

doi:10.1021/jm049614v

Cited by 204 publications

(310 citation statements)

References 52 publications

(153 reference statements)

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“…These results correlate with those reported in the literature. [28][29][30][31] The structures of compounds and their inhibition potencies for FAAH and MAGL-like enzyme activity are presented in the 41 Compounds 11, 12, and 13 as well as the corresponding sulfur analogs (19,20, and 21) were found to have a trend for increasing potency for FAAH with increasing length of the alkyl group. It was noteworthy that compounds 18 and 26, containing 3-methylbenzyl carbamate, had clearly higher inhibition activity against MAGL-like enzyme activity compared to the other compounds in this series.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors

et al. 2007

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Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase, which catalyzes the hydrolysis of the endocannabinoid N-arachidonoylethanolamide to arachidonic acid and ethanolamine. FAAH also hydrolyzes another endocannabinoid, 2-arachidonoylglycerol (2-AG). However, 2-AG has been assumed to be hydrolyzed mainly by monoacylglycerol lipase (MAGL) or a MAGL-like enzyme. Inhibition of FAAH or MAGL activity might lead to beneficial effects in many physiological disorders such as pain, inflammation, and anxiety due to increased endocannabinoid-induced activation of cannabinoid receptors CB1 and CB2. In the present study, a total of 34 novel compounds were designed, synthesized, characterized, and tested against FAAH and MAGL-like enzyme activity. Altogether, 16 compounds were found to inhibit FAAH with half-maximal inhibition concentrations (IC 50 ) between 28 and 380 nM. All the active compounds belong to the structural family of carbamates. Compounds 14 and 18 were found to be the most potent FAAH inhibitors, which may serve as lead structures for novel FAAH inhibitors.

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Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors

et al. 2007

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“…In contrast, URB597 binds irreversibly to FAAH and AM404 is not selective. OL-135 was synthesized as described previously (Boger et al, 2005). All drugs were dissolved in a 1:1 mixture of absolute ethanol and alkamuls-620 (Rhone-Poulenc, Princeton, NJ) and diluted with saline to a final ratio of 1:1:18 (ethanol:alkamuls:saline).…”

Section: Drugsmentioning

confidence: 99%

Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task

Varvel

Wise

Niyuhire

et al. 2006

Neuropsychopharmacol

154

113

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Recent reports have demonstrated that disruption of CB 1 receptor signaling impairs extinction of learned responses in conditioned fear and Morris water maze paradigms. Here, we test the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide through either genetic deletion or pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH) will potentiate extinction in a fixed platform water maze task. FAAH (À/À) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption, but did exhibit a significant increase in the rate of extinction. Unexpectedly, FAAHcompromised mice also exhibited a significant increase in acquisition rate. The CB 1 receptor antagonist SR141716 (rimonabant) when given alone had no effects on acquisition, but disrupted extinction. Additionally, SR141716 blocked the effects of OL-135 on both acquisition and extinction. Collectively, these results indicate that endogenous anandamide plays a facilitatory role in extinction through a CB 1 receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, D 9 -tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB 1 receptor agonist in facilitating extinction. More generally, these findings suggest that FAAH inhibition represents a promising pharmacological approach to treat psychopathologies hallmarked by an inability to extinguish maladaptive behaviors, such as post-traumatic stress syndrome and obsessive-compulsive disorder.

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“…26 Although there are no other characterized mammalian members of the serine hydrolase family that bear the amidase signature sequence and its unusual Ser-Ser-Lys catalytic triad and no resulting close family of enzymes against which to counter screen the candidate inhibitors, a close collaboration with Professor Cravatt led to the implementation of a proteomewide assay capable of simultaneously interrogating all mammalian serine hydrolases applicable to assessing the selectivity of reversible enzyme inhibitors. 35 This assay, which requires no modification of the inhibitor, no purified protein for conventional substrate assay, no knowledge of candidate off-site targets or even the function or substrate of the enzymes, can globally detect, identify, and quantitate all potential competitive enzyme targets in the human proteome for such inhibitors.…”

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confidence: 99%

Exploration of a fundamental substituent effect of α-ketoheterocycle enzyme inhibitors: Potent and selective inhibitors of fatty acid amide hydrolase

DeMartino

Garfunkle

Hochstatter

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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A series of C4 substituted α-ketooxazoles were examined as inhibitors of the serine hydrolase fatty acid amide hydrolase in efforts that further define and generalize a fundamental substituent effect on enzyme inhibitory potency. Thus, a plot of the Hammett σ m versus -log K i provided a linear correlation (R 2 = 0.90) with a slope of 3.37 (ρ = 3.37) that is of a magnitude that indicates the electronwithdrawing character of the substituent dominates its effects (a one unit change in σ m provides a >1000-fold change in K i ).Fatty acid amide hydrolase (FAAH) 1,2 is the enzyme that serves to hydrolyze endogenous lipid amides 3,4 including anandamide (1a) 5 and oleamide (1b), 6 Figure 1. Its distribution is consistent with its role in degrading and regulating such signaling fatty acid amides at their sites of action. 3 Although it is a member of the amidase signature family of serine hydrolases, for which there a number of prokaryotic enzymes, it is currently the only characterized mammalian enzyme bearing the family's unusual Ser-Ser-Lys catalytic triad. 7,8 Due to the therapeutic potential of inhibiting FAAH 9 especially for the treatment of pain, 10 inflammation, 11 or sleep disorders, 12 there has been increasing interest in the development of selective and potent inhibitors of the enzyme. 9 Early studies shortly following the initial discovery and characterization of FAAH led to the demonstration that the endogenous sleepinducing molecule 2-octyl α-bromoacetoacetate is an effective FAAH inhibitor, 13 the disclosure of a series of nonselective, reversible inhibitors bearing an electrophilic ketone (e.g., trifluoromethyl ketone-based inhibitors), 14,15 and the reports of a set of irreversible inhibitors 16 (e.g., fluorophosphonates and sulfonyl fluorides). To date, two classes of inhibitors have been disclosed that provide opportunities for the development of inhibitors with therapeutic potential. One class is the reactive aryl carbamates and ureas 17-24 that irreversibly acylate a FAAH active site serine. 25 A second class is the α-ketoheterocycle-based inhibitors 26-29 that bind to FAAH via reversible hemiketal formation with an active site serine. Many of these latter competitive inhibitors are not only potent and extraordinarily selective for FAAH versus other mammalian serine hydrolases, but members of this class have been shown to be efficacious analgesics in vivo. 28In the course of these latter studies, we disclosed a fundamental substituent effect in which a well-defined correlation between the electronic character of a para substituent (Hammett σ p ) and the inhibitor potency (−log K i ) was observed. 27 Thus, the inhibitor potency was found to *Corresponding author: email boger@scripps.edu. Whereas the former para substituents are directly conjugated with the electrophilic carbonyl, the meta substituents would exert their effects through their inductive electron-withdrawing properties. Moreover and although intuitive expectations might suggest that such a nonconjugated substituent effect might...

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Discovery of a Potent, Selective, and Efficacious Class of Reversible α-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Effective as Analgesics

Cited by 204 publications

References 52 publications

Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors

Design, Synthesis, and In Vitro Evaluation of Carbamate Derivatives of 2-Benzoxazolyl- and 2-Benzothiazolyl-(3-hydroxyphenyl)-methanones as Novel Fatty Acid Amide Hydrolase Inhibitors

Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task

Exploration of a fundamental substituent effect of α-ketoheterocycle enzyme inhibitors: Potent and selective inhibitors of fatty acid amide hydrolase

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