Design, synthesis, and structure–activity relationships of 1,3,4-oxadiazol-2(3H)-ones as novel FAAH inhibitors

Kiss, László E.; Ferreira, Humberto; Беляев, А. Н.; Torrão, Leonel; Bonifácio, Maria João; Learmonth, David A.

doi:10.1039/c1md00136a

Cited by 17 publications

(7 citation statements)

References 11 publications

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“…Fatty acid amide hydrolase activity was determined by measuring the formation of 3 H‐ethanolamine from tritium ( 3 H)‐labelled AEA in Wistar rat brain membranes prepared in house as described elsewhere (Kiss et al, ; Kiss et al, ). The reaction mixture (total volume of 200 μl) contained substrate solution (2 μM of AEA + 5 nM of 3 H‐AEA + 0.1% fatty acid‐free BSA), 10 μg of protein, in fatty acid amide hydrolase incubation buffer (1 mM of EDTA and 10 mM of Tris, pH 7.6) and test compounds (BIA 10‐2474, PF‐04457845 or JNJ‐42165279) ranging from 1 nM to 10 μM.…”

Section: Methodsmentioning

confidence: 99%

Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10‐2474

Bonifácio¹,

Sousa²,

Aires³

et al. 2020

British J Pharmacology

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Background and Purpose: In 2016, one person died and four others had mild-tosevere neurological symptoms during a phase I trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474.Experimental Approach: Pharmacodynamic and pharmacokinetic studies were performed with BIA 10-2474, PF-04457845 and JNJ-42165279 using mice, rats and human FAAH expressed in COS cells. Selectivity was evaluated by activity-based protein profiling (APBB) in rats. BIA 10-2474 effect in stroke-prone spontaneously hypertensive rats (SHRSP) was investigated.Key Results: BIA 10-2474 was 10-fold less potent than PF-04457845 in inhibiting human FAAH in situ but inhibited mouse brain and liver FAAH with ED 50 values of 13.5 and 6.2 μgÁkg −1 , respectively. Plasma and brain BIA 10-2474 levels were consistent with in situ potency and neither BIA 10-2474 nor its metabolites accumulated following repeat administration. FAAH and α/β-hydrolase domain containing 6 were the primary targets of BIA 10-2474 and, at higher exposure levels, ABHD11, PNPLA6, PLA2G15, PLA2G6 and androgen-induced protein 1. At 100 mgÁkg −1 for 28 days, the level of several lipid species containing arachidonic acid increased. Daily treatment of SHRSP with BIA 10-2474 did not affect mortality rate or increased the incidence of haemorrhage or oedema in surviving animals.Conclusions and Implications: BIA 10-2474 potently inhibits FAAH in vivo, similarly to PF-04457845 and interacts with a number of lipid processing enzymes, some previously identified in human cells as off-targets particularly at high levels of exposure.These interactions occurred at doses used in toxicology studies, but the implication of these off-targets in the clinical trial accident remains unclear.Abbreviations: 2-AG, 2-arachidonoylglycerol; AA, arachidonic acid; ABHD6, α/β-hydrolase domain containing 6; ABPP, activity-based protein profiling; AEA, anandamide; AIG1, androgeninduced protein 1; BCRP, breast cancer resistance protein; CES, carboxyl esterase; CYP, cytochrome P450; DAG, diacylglycerol; FAAH, fatty acid amide hydrolase; LIPE, lipase E; MATE, multidrug and toxin extrusion; MDR, multidrug resistance; OAT, organic anion transporter; OCT, organic cation transporter; OEA, oleoylethanolamide; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PEA, palmitoylethanolamide; P-gp, P-glycoprotein; PLA2G15, PLA 2 Group 15; PLA2G6, PLA 2 Group 6; PNPLA6, patatin-like phospholipase domain containing 6; SHRSP, Spontaneously hypertensive rats stroke prone; TAMRA-FP, tetramethylrhodamine-fluorophosphonate.

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Section: Methodsmentioning

confidence: 99%

Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10‐2474

Bonifácio¹,

Sousa²,

Aires³

et al. 2020

British J Pharmacology

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“…Conventional methods [12,17] for the synthesis of these compounds involved in toxic phosgene or CO and a tedious multi-step synthetic process. From the viewpoints of simplicity, cost effectiveness, nontoxicity and sustainability, using carbon dioxide to replace phosgene or CO for the direct one-step synthesis of 1,3,4-oxadiazol-2(3H)-one derivatives seems to be more attractive and more challenging.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

A novel electrochemical conversion of CO 2 with aryl hydrazines and paraformaldehyde into 1,3,4-oxadiazol-2(3 H )-one derivatives in one step

Yang

Lai

Jiang

et al. 2016

Electrochemistry Communications

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“…FAAH activity was evaluated in these preparations. Enzyme assays:F AAH activity in vitro and in tissues preparations from treated animals was evaluated essentially as described by Kiss et al [44] In brief, for compound evaluation in vitro reaction mix (total volume of 200 mL) contained:2mm AEA (2 mm AEA + 5nm [ 3 H]AEA), 0.1 %f atty acid free BSA, 5 mgr at brain membrane preparation and the compound to evaluate in 1mm EDTA, 10 mm Tris pH 7.6. After a1 5min pre-incubation period at 37 8C, reaction was started by the addition of the substrate solution (cold AEA + radiolabeled AEA + BSA).…”

Section: Discussionmentioning

confidence: 99%

“…Enzyme assays : FAAH activity in vitro and in tissues preparations from treated animals was evaluated essentially as described by Kiss et al . In brief, for compound evaluation in vitro reaction mix (total volume of 200 mL) contained: 2 μ m AEA (2 μ m AEA+5 n m [ 3 H]AEA), 0.1 % fatty acid free BSA, 5 μg rat brain membrane preparation and the compound to evaluate in 1 m m EDTA, 10 m m Tris pH 7.6.…”

Section: Methodsmentioning

confidence: 99%

Discovery of a Potent, Long‐Acting, and CNS‐Active Inhibitor (BIA 10‐2474) of Fatty Acid Amide Hydrolase

et al. 2018

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Fatty acid amide hydrolase (FAAH) can be targeted for the treatment of pain associated with various medical conditions. Herein we report the design and synthesis of a novel series of heterocyclic-N-carboxamide FAAH inhibitors that have a good alignment of potency, metabolic stability and selectivity for FAAH over monoacylglycerol lipase (MAGL) and carboxylesterases (CEs). Lead optimization efforts carried out with benzotriazolyl- and imidazolyl-N-carboxamide series led to the discovery of clinical candidate 8 l (3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide; BIA 10-2474) as a potent and long-acting inhibitor of FAAH. However, during a Phase I clinical trial with compound 8 l, unexpected and unpredictable serious neurological adverse events occurred, affecting five healthy volunteers, including the death of one subject.

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Design, synthesis, and structure–activity relationships of 1,3,4-oxadiazol-2(3H)-ones as novel FAAH inhibitors

Abstract: Novel 5-aryloxy substituted 3-phenyl-1,3,4-oxadiazol-2(3H)-ones were prepared and identified as potent inhibitors of FAAH. In vitro SAR are discussed. Structural variations of the selected lead compound were explored in order to optimise in vivo efficacy and selectivity.

Cited by 17 publications

References 11 publications

Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10‐2474

Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10‐2474

A novel electrochemical conversion of CO 2 with aryl hydrazines and paraformaldehyde into 1,3,4-oxadiazol-2(3 H )-one derivatives in one step

Discovery of a Potent, Long‐Acting, and CNS‐Active Inhibitor (BIA 10‐2474) of Fatty Acid Amide Hydrolase

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