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Feb, 2021;25 (1): 45-53.

Novel amide derivatives of 3-phenylglutaric acid as potent soluble epoxide hydrolase inhibitors.

Elham Rezaee, Somayeh Minaei Amrolah, Maryam Nazari, Sayyed Abbas Tabatabai
Author Information
  1. Elham Rezaee: Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, No. 2660, Vali-e-Asr, Tehran, 1991953381, Iran.
  2. Somayeh Minaei Amrolah: Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, No. 2660, Vali-e-Asr, Tehran, 1991953381, Iran.
  3. Maryam Nazari: Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, No. 2660, Vali-e-Asr, Tehran, 1991953381, Iran.
  4. Sayyed Abbas Tabatabai: Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, No. 2660, Vali-e-Asr, Tehran, 1991953381, Iran. sa_tabatabai@sbmu.ac.ir. ORCID
PMID: 31873869 DOI: 10.1007/s11030-019-10023-y

Abstract

Soluble epoxide hydrolase (sEH) enzyme plays an important role in the metabolism of endogenous chemical mediators, epoxyeicosatrienoic acids, which are involved in the regulation of blood pressure and inflammation. According to the pharmacophoric model suggested for sEH inhibitors, some new amide-based derivatives of 3-phenylglutaric acid were designed, synthesized and biologically evaluated. Docking study illustrated that the amide group as a primary pharmacophore had a suitable distance from the three amino acids of Tyr383, Tyr466 and Asp335 for effective hydrogen binding. Most of the compounds showed moderate to high sEH inhibitory activities in in vitro test in comparison with 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid, as a potent urea-based sEH inhibitor. Compound 6o with phenethyl in R position exhibited the highest activity with IC value of 0.5 nM. In this study, some new amide-based derivatives of 3-phenylglutaric acid were designed, synthesized and biologically evaluated. Most of the synthesized compounds provided nanomolar range inhibition against sEH enzyme. The best observed IC value was 0.5 nM. Incorporating a carboxylic moiety into these structures by forming carboxylate salts would increase the solubility and improving physicochemical properties.

Keywords

Biological evaluation Phenylglutaric acid Soluble epoxide hydrolase inhibitor Synthesis

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Grants

  1. 7765/Shahid Beheshti University of Medical Sciences
  2. 8457/Shahid Beheshti University of Medical Sciences

MeSH Term

Amides
Enzyme Inhibitors
Epoxide Hydrolases
Glutarates
Humans
Lauric Acids
Models, Molecular
Solubility
Structure-Activity Relationship

Chemicals

Amides
Enzyme Inhibitors
Glutarates
Lauric Acids
lauric acid
Epoxide Hydrolases
glutaric acid
Journal Article

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