Lucarini Elena, D'Antogiovanni Vanessa, Antonioli Luca, Ghelardini Carla, Di Cesare Mannelli Lorenzo, Ferraroni Marta, Locuoco Maria, Capperucci Antonella, Tanini Damiano, Angeli Andrea, Supuran Claudiu T
Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section, University of Florence, 6-50139 Florence, Italy.
Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.
ACS Med Chem Lett. 2024 Aug 14;15(9):1559-1565. doi: 10.1021/acsmedchemlett.4c00284. eCollection 2024 Sep 12.
Carbonic anhydrase (CA) inhibitors represent intriguing tools for treating pain. This study aims at studying the pharmacological profile of chalcogen bioisosteres of aspirin, as inhibitors of CA isoforms (hCA I, II, IV, VII, IX, and XII). Our results show that selenoaspirin () displayed markedly superior inhibitory potency across all tested isoforms compared to thioaspirin () and aspirin, with a strong selectivity against the isoform CA IX. X-ray crystallography confirmed that both compounds bind effectively within the active site of hCA II, revealing unique structural characteristics compared to those of aspirin. In a preclinical model of inflammatory pain, compound exhibited a longer lasting antihyperalgesic effect than aspirin, though with a lower potency. Conversely, compound exhibited both lower potency and efficacy than aspirin in reducing pain, which entailed both adverse effects. Nevertheless, the therapeutic potential of chalcogen-based aspirin derivatives as novel CA inhibitors deserves to be further explored for clinical applications.
碳酸酐酶（CA）抑制剂是治疗疼痛的有趣工具。本研究旨在研究阿司匹林硫属生物电子等排体作为CA同工型（hCA I、II、IV、VII、IX和XII）抑制剂的药理学特征。我们的结果表明，与硫代阿司匹林（）和阿司匹林相比，硒代阿司匹林（）在所有测试的同工型中均表现出明显更高的抑制效力，对同工型CA IX具有很强的选择性。X射线晶体学证实，这两种化合物均能有效结合在hCA II的活性位点内，与阿司匹林相比显示出独特的结构特征。在炎症性疼痛的临床前模型中，化合物 表现出比阿司匹林更持久的抗痛觉过敏作用，尽管效力较低。相反，化合物 在减轻疼痛方面表现出比阿司匹林更低的效力和疗效，这都带来了不良反应。然而，基于硫属元素的阿司匹林衍生物作为新型CA抑制剂的治疗潜力值得进一步探索其临床应用。
