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 08028, Spain.
Animal Behavior Research Unit, Scientific Instrumentation Center, Parque Tecnológico de Ciencias de la Salud, University of Granada, Armilla, Granada 18100, Spain.
J Med Chem. 2022 Oct 27;65(20):13660-13680. doi: 10.1021/acs.jmedchem.2c00515. Epub 2022 Oct 12.
The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field.
可溶性环氧化物水解酶（sEH）已被提议作为治疗多种疾病的药理学靶点，包括与疼痛相关的疾病。在此，我们报告了围绕新的苯并同金刚烷基 sEH 抑制剂（sEHI）的进一步药物化学研究，以改善之前命中化合物的药物代谢和药代动力学特性。经过广泛的体外筛选级联、分子建模和体内药代动力学研究，两种候选化合物在辣椒素诱导的痛觉过敏的小鼠模型中进行了体内评估。这两种化合物以剂量依赖性方式表现出抗痛觉过敏作用。此外，最有效的化合物在环磷酰胺诱导的膀胱炎的小鼠模型中表现出强大的镇痛功效，该模型是内脏疼痛的一种成熟模型。总体而言，这些结果表明膀胱疼痛综合征是 sEHI 的一个新的可能适应证，为它们在内脏疼痛领域开辟了新的应用范围。
