Exploring the size of the lipophilic unit of the soluble epoxide hydrolase inhibitors

Bioorg Med Chem. 2019 Oct 15;27(20):115078. doi: 10.1016/j.bmc.2019.115078.

Sandra Codony ¹, Elena Valverde ¹, Rosana Leiva ¹, José Brea ², M Isabel Loza ², Christophe Morisseau ³, Bruce D Hammock ³, Santiago Vázquez ⁴

Affiliations

1 Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, Barcelona E-08028, Spain.
2 Innopharma Screening Platform, Biofarma Research Group, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidad de Santiago de Compostela, Spain.
3 Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
4 Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, Barcelona E-08028, Spain. Electronic address: svazquez@ub.edu.

PMID: 31488357 DOI: 10.1016/j.bmc.2019.115078

Abstract

Soluble Epoxide Hydrolase (sEH) inhibitors are potential drugs for several diseases. Adamantyl ureas are excellent sEH inhibitors but have limited metabolic stability. Herein, we report the effect of replacing the adamantane group by alternative polycyclic hydrocarbons on sEH inhibition, solubility, permeability and metabolic stability. Compounds bearing smaller or larger polycyclic hydrocarbons than adamantane yielded all good inhibition potency of the human sEH (0.4 ≤ IC₅₀ ≤ 21.7 nM), indicating that sEH is able to accommodate inhibitors of very different size. Human liver microsomal stability of diamantane containing inhibitors is lower than that of their corresponding adamantane counterparts.

Keywords

Adamantane; Inhibitor; Isocyanate; Soluble epoxide hydrolase; Urea.

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