Laboratori de Quı́mica Farmacèutica (Unitat Associada al CSIC), Departament de Farmacologia, Toxicologia i Quı́mica Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain.
Pharmacology, Departament de Farmacologia, Toxicologia i Quı́mica Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain.
J Med Chem. 2020 Sep 10;63(17):9237-9257. doi: 10.1021/acs.jmedchem.0c00310. Epub 2020 Aug 25.
pharmacological inhibition of soluble epoxide hydrolase (sEH) reduces inflammatory diseases, including acute pancreatitis (AP). Adamantyl ureas are very potent sEH inhibitors, but the lipophilicity and metabolism of the adamantane group compromise their overall usefulness. Herein, we report that the replacement of a methylene unit of the adamantane group by an oxygen atom increases the solubility, permeability, and stability of three series of urea-based sEH inhibitors. Most of these oxa-analogues are nanomolar inhibitors of both the human and murine sEH. Molecular dynamics simulations rationalize the molecular basis for their activity and suggest that the presence of the oxygen atom on the adamantane scaffold results in active site rearrangements to establish a weak hydrogen bond. The 2-oxaadamantane , which has a good solubility, microsomal stability, and selectivity for sEH, was selected for further and studies in models of cerulein-induced AP. Both in prophylactic and treatment studies, diminished the overexpression of inflammatory and endoplasmic reticulum stress markers induced by cerulein and reduced the pancreatic damage.
药物抑制可水解型环氧合酶（sEH）可减少炎症性疾病，包括急性胰腺炎（AP）。金刚烷脲类化合物是非常有效的 sEH 抑制剂，但金刚烷基团的亲脂性和代谢会影响其整体效果。本研究报告称，用氧原子取代金刚烷基团中的亚甲基单元会增加基于脲的 sEH 抑制剂三个系列的溶解度、通透性和稳定性。这些氧杂类似物中的大多数对人和鼠 sEH 均为纳摩尔级抑制剂。分子动力学模拟为其活性提供了合理的解释，并表明在金刚烷支架上存在氧原子会导致活性位点发生重排，从而建立弱氢键。2-氧杂金刚烷具有良好的水溶性、微粒体稳定性和 sEH 选择性，被选中用于进一步研究和治疗亮抑蛋白酶肽诱导的 AP 模型。在预防性和治疗性研究中，均能减轻亮抑蛋白酶肽诱导的炎症和内质网应激标志物的过度表达，并减轻胰腺损伤。
