Structure-guided inhibitor design for human FAAH by interspecies active site conversion

Mileni, Mauro; Johnson, Douglas S.; Wang, Zhigang; Everdeen, Daniel S.; Liimatta, Marya; Pabst, Brandon; Bhattacharya, Keshab; Nugent, Richard A.; Kamtekar, S.; Cravatt, Benjamin F.; Ahn, Kay; Stevens, Raymond C.

doi:10.1073/pnas.0806121105

Cited by 140 publications

(205 citation statements)

References 35 publications

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“…The overall structure of the FAAH protein resembles those previously reported (36)(37)(38)(39)(40)(41). The core structure of the FAAH monomer adopts an α/β fold with a twisted 11-strand β-sheet in the center and 24 α-helices surrounding the sheet ( Fig.…”

Section: Resultssupporting

confidence: 62%

“…These recently reported inhibitors are highly potent and selective, with some of them demonstrating in vivo efficacy (26,35). The inhibitor cocrystal structures were also reported for MAFP with rat FAAH, and PF-750, PF-3845, URB597, and OL-135 with humanized rat FAAH (36)(37)(38)(39)(40)(41). However, like ATMK and MAFP, most of the inhibitors disclosed so far rely on covalent modification of the catalytic serine 241 in the active site, either by forming a stable acyl-enzyme adduct or a hemi-acetal with Ser241, which is stabilized by the oxyanion hole.…”

Section: Discovery and Molecular Basis Of Potent Noncovalent Inhibitomentioning

confidence: 97%

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Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH)

Min¹,

Thibault²,

Porter

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Fatty acid amide hydrolase (FAAH), an amidase-signature family member, is an integral membrane enzyme that degrades lipid amides including the endogenous cannabinoid anandamide and the sleep-inducing molecule oleamide. Both genetic knock out and pharmacological administration of FAAH inhibitors in rodent models result in analgesic, anxiolytic, and antiinflammatory phenotypes. Targeting FAAH activity, therefore, presents a promising new therapeutic strategy for the treatment of pain and other neurological-related or inflammatory disorders. Nearly all FAAH inhibitors known to date attain their binding potency through a reversible or irreversible covalent modification of the nucleophile Ser241 in the unusual Ser-Ser-Lys catalytic triad. Here, we report the discovery and mechanism of action of a series of ketobenzimidazoles as unique and potent noncovalent FAAH inhibitors. Compound 2, a representative of these ketobenzimidazoles, was designed from a series of ureas that were identified from highthroughput screening. While urea compound 1 is characterized as an irreversible covalent inhibitor, the cocrystal structure of FAAH complexed with compound 2 reveals that these ketobenzimidazoles, though containing a carbonyl moiety, do not covalently modify Ser241. These inhibitors achieve potent inhibition of FAAH activity primarily from shape complementarity to the active site and through numerous hydrophobic interactions. These noncovalent compounds exhibit excellent selectivity and good pharmacokinetic properties. The discovery of this distinctive class of inhibitors opens a new avenue for modulating FAAH activity through nonmechanism-based inhibition.structure-based design | medicinal chemistry F atty acid amides (FAAs) represent a class of lipid signaling molecules that modulate a wide range of physiological processes in the central nervous system (1). As a prominent member of the FAA family, the endogenous cannabinoid anandamide, also known as N-arachidonoylethanolamine or AEA, produces its neurotransmitting effects by binding to and activating two G protein-coupled cannabinoid receptors (i.e., CB1 in the central nervous system and CB2 in the periphery) (2). Previous studies have shown that the effects of anandamide include neurological pain suppression, antiproliferation of cancer cells, enhancement of feeding behavior, and generation of motivation and pleasure (3-7). Endogenous oleamide (cis-9,10-octadecenoamide), also known as a sleep-inducing molecule in the FAA family, was found in the cerebrospinal fluid of sleep-deprived animals (8, 9). In addition, other neurological activities have been associated with oleamide, including regulation of memory processes, body temperature, and locomotor activity (10-12). However, the actions of these lipid messengers are ephemeral because of the hydrolytic activity of a number of enzymes including fatty acid amide hydrolase (FAAH). FAAH is an integral membrane enzyme that degrades these lipid amides (13-17) and thus terminates their activities. Inhibition of FAAH activity provi...

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Section: Resultssupporting

confidence: 62%

Section: Discovery and Molecular Basis Of Potent Noncovalent Inhibitomentioning

confidence: 97%

Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH)

Min¹,

Thibault²,

Porter

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…In particular, in this approach, we focused on exploring the differences arising from the protein-ligand interactions of the recognition process, as it can be assumed that the reactivity of the compounds is in similar level within the enantiomeric pairs. It should be noted that a crystal structure of partially humanized rat FAAH with a druglike inhibitor PF-750 [41] (PDB code 2VYA) has been published recently. This structure shows structural rearrangements in the substrate access channel region with Phe432 flipping into the acyl chain binding (ACB) channel.…”

Section: Resultsmentioning

confidence: 99%

Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields

Myllymäki¹,

Käsnänen

Kataja³

et al. 2009

European Journal of Medicinal Chemistry

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Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are the main enzymes responsible for the hydrolysis of endogenous cannabinoids N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively. Phenyl alkylcarbamates are FAAH inhibitors with anxiolytic and analgesic activities in vivo. Herein we present for the first time the synthesis and biological evaluation of a series of chiral 3-(2-oxazoline)-phenyl N-alkylcarbamates as FAAH inhibitors. Furthermore, the structural background of chirality on the FAAH inhibition is explored by analyzing the protein-ligand interactions. Remarkably, 10-fold difference in potency was observed for (R)-and (S)-derivatives of 3-(5-methyl-4,5-dihydrooxazol-2-yl)phenyl cyclohexylcarbamate (6a vs. 6b). Molecular modelling indicated an important interaction between the oxazoline nitrogen and FAAH active site.

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“…30 Urea derivatives as prepared by Pfizer, Takeda, and us operate via a similar mechanism but have aromatic amines as leaving groups rather than alcohols or phenols. 31 40 Amgen, 41 Renovis, 42 and Johnson and Johnson. 43 Several compounds have been profiled to some degree in the clinic.…”

Section: T He Fatty Acid Amide Hydrolases (Faah and Faah-2)mentioning

confidence: 99%

Preclinical Characterization of the FAAH Inhibitor JNJ-42165279

Keith

Tichenor

et al. 2015

ACS Med. Chem. Lett.

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The pre-clinical characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good physical, ADME, and PD properties of JNJ-42165279 supported it entering the clinical portfolio. KEYWORDS: FAAH, covalent, ethanolamides, enzyme, anandamide T he fatty acid amide hydrolases 1,2 interrupt the actions, through degradation, of a variety of endogenous lipid signaling molecules.3 FAAH rapidly degrades several fatty acid ethanolamides, including FAAH's primary substrate, AEA (N-arachidonyl ethanolamide or anandamide), 4 PEA (N-palmitoyl ethanolamide), 5,6 and OEA (N-oleoyl ethanolamide).7 In contrast, FAAH-2 catabolizes ethanolamides less efficiently, but will hydrolyze long-chain primary amides. The likely source of AEA's analgesic pharmacology is its ability to agonize the cannabinoid receptor CB 1 .8−10 However, AEA is synthesized on demand and then rapidly broken down locally, which mitigates the side-effects observed as a result of systemic CB 1 agonism (e.g., Δ 9 THC pharmacology). As AEA is synthesized in a localized manner, one might hypothesize that inhibiting FAAH could lead to elevated concentrations of AEA in relevant tissues. Indeed, prior reports have described an increase in AEA levels in the plasma and brains 11−14 of rats and in the plasma of humans upon inhibition of FAAH.Small molecule interruption of FAAH activity has been examined in numerous laboratories (Figure 1)

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Structure-guided inhibitor design for human FAAH by interspecies active site conversion

Cited by 140 publications

References 35 publications

Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH)

Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH)

Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields

Preclinical Characterization of the FAAH Inhibitor JNJ-42165279

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