Synthesis and structure–activity relationships of ionizable 1,3,4-oxadiazol-2(3<i>H</i>)-ones as peripherally selective FAAH inhibitors with improved aqueous solubility

Беляев, А. Н.; Ferreira, Humberto; Learmonth, David A.; Bonifácio, Maria João; Torrão, Leonel; Pires, Nuno; Soares-da-Silva, Patrı́cio; Kiss, László E.

doi:10.1515/pac-2016-0104

Cited by 3 publications

(3 citation statements)

References 24 publications

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“…Fatty acid amide hydrolase activity in brain and liver homogenates was evaluated essentially as described (Beliaev et al, ) and as above. The amount of protein in the assays was 15 μg (brain) or 5 μg (liver) and there was no compound added.…”

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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“…Unfortunately, there is minimal information about the structure–activity relationship studies performed on a series of different types of fatty acid amide hydrolase inhibitors [ 9 ]. Käsnänen et al synthesized a series of meta-substituted phenolic N-alkyl/aryl carbamates.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the modeling set comprised only compounds containing the 1,3,4-oxadiazol-2-one moiety, synthesized by Patel et al [ 14 , 15 ]. Among the diverse scaffolds utilized for the development of FAAH inhibitors, 1,3,4-oxadiazol-2-one has gained recent attention in the development of serine hydrolase inhibitors, including FAAH [ 9 , 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. The modeling set comprised novel 1,3,4-oxadiazol-2-ones derivatives ( Table 1 ), previously tested for their inhibitory activity against FAAH [ 14 , 15 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Docking-Based 3D-QSAR Studies for 1,3,4-oxadiazol-2-one Derivatives as FAAH Inhibitors

Zięba

Laitinen

Patel

et al. 2021

IJMS

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This work aimed to construct 3D-QSAR CoMFA and CoMSIA models for a series of 31 FAAH inhibitors, containing the 1,3,4-oxadiazol-2-one moiety. The obtained models were characterized by good statistical parameters: CoMFA Q2 = 0.61, R2 = 0.98; CoMSIA Q2 = 0.64, R2 = 0.93. The CoMFA model field contributions were 54.1% and 45.9% for steric and electrostatic fields, respectively. In the CoMSIA model, electrostatic, steric, hydrogen bond donor, and hydrogen acceptor properties were equal to 34.6%, 23.9%, 23.4%, and 18.0%, respectively. These models were validated by applying the leave-one-out technique, the seven-element test set (CoMFA r2test-set = 0.91; CoMSIA r2test-set = 0.91), a progressive scrambling test, and external validation criteria developed by Golbraikh and Tropsha (CoMFA r20 = 0.98, k = 0.95; CoMSIA r20 = 0.98, k = 0.89). As the statistical significance of the obtained model was confirmed, the results of the CoMFA and CoMSIA field calculation were mapped onto the enzyme binding site. It gave us the opportunity to discuss the structure–activity relationship based on the ligand–enzyme interactions. In particular, examination of the electrostatic properties of the established CoMFA model revealed fields that correspond to the regions where electropositive substituents are not desired, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one moiety. This highlights the importance of heterocycle, a highly electronegative moiety in this area of each ligand. Examination of hydrogen bond donor and acceptor properties contour maps revealed several spots where the implementation of another hydrogen-bond-donating moiety will positively impact molecules’ binding affinity, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one ring. On the other hand, there is a large isopleth that refers to the favorable H-bond properties close to the terminal phenoxy group of a ligand, which means that, generally speaking, H-bond acceptors are desired in this area.

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A perspective review on fatty acid amide hydrolase (FAAH) inhibitors as potential therapeutic agents

Tripathi

2020

European Journal of Medicinal Chemistry

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Synthesis and structure–activity relationships of ionizable 1,3,4-oxadiazol-2(3H)-ones as peripherally selective FAAH inhibitors with improved aqueous solubility

Cited by 3 publications

References 24 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

Docking-Based 3D-QSAR Studies for 1,3,4-oxadiazol-2-one Derivatives as FAAH Inhibitors

A perspective review on fatty acid amide hydrolase (FAAH) inhibitors as potential therapeutic agents

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