Design, microwave-assisted synthesis, biological evaluation and molecular modeling studies of 4-phenylthiazoles as potent fatty acid amide hydrolase inhibitors.
docking experiments
enzyme inhibition
homology modeling
microwave-assisted synthesis
structure-activity relationship study
Journal
Chemical biology & drug design
ISSN: 1747-0285
Titre abrégé: Chem Biol Drug Des
Pays: England
ID NLM: 101262549
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
20
10
2019
revised:
03
01
2020
accepted:
06
02
2020
pubmed:
16
2
2020
medline:
13
5
2021
entrez:
16
2
2020
Statut:
ppublish
Résumé
Endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are endogenous lipids that activate cannabinoid receptors. Activation of these receptors produces anti-inflammatory and analgesic effects. Fatty acid amide hydrolase (FAAH) is a membrane enzyme that hydrolases endocannabinoids; thus, inhibition of FAAH represents an attractive approach to develop new therapeutics for treating inflammation and pain. Previously, potent rat FAAH inhibitors containing 2-naphthyl- and 4-phenylthiazole scaffolds were identified, but up to the present time, very little structure-activity relationship studies have been performed on these moieties. We designed and synthesized several analogs containing these structural motifs and evaluated their inhibition potencies against human FAAH enzyme. In addition, we built and validated a homology model of human FAAH enzyme and performed docking experiments. We identified several inhibitors in the low nanomolar range and calculated their ADME predicted values. These FAAH inhibitors represent promising drug candidates for future preclinical in vivo studies.
Substances chimiques
Enzyme Inhibitors
0
Thiazoles
0
Amidohydrolases
EC 3.5.-
fatty-acid amide hydrolase
EC 3.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
534-547Informations de copyright
© 2020 John Wiley & Sons A/S.
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