Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece.
School of Health Science and Education, Department of Nutrition and Dietetics, Harokopio University, Athens, Greece.
J Biomol Struct Dyn. 2022;40(24):13889-13900. doi: 10.1080/07391102.2021.1996461. Epub 2021 Nov 18.
Despite the scientific progression in the prevention and treatment of cardiovascular diseases (CVDs) they remain the leading cause of mortality and disability worldwide. The classic treatment involves the simultaneous dosing of two antiplatelet drugs, aspirin and clopidogrel/prasugrel. However, besides drug resistance, severe side effects have been also manifested including acute bleeding and toxicity. Thus, new therapeutic agents with enhanced efficacy and diminished side effects are of importance. Towards this end, omega-3 (ω-3) fatty acids have demonstrated potent efficacy against CVDs through inhibiting platelet aggregation that bears a pivotal role in atherothrombosis. Another factor that displays a critical role in the pathogenesis of cardiovascular diseases is the renin-angiotensin system (RAS), and especially the ATR blocker losartan that has been reported to exert antiplatelet activity mediated by this receptor. Along these lines, we envisaged developing a molecular hybrid consisted of docosahexaenoic acid (ω-3 fatty acid) and losartan, that could exert a notable antiplatelet effect against CVDs. The design and synthesis of the new DHA-losartan hybrid, designated DHA-L, bestowed with the additive properties of the parent compounds, is reported. studies were first exploited to validate the potential of DHA-L to retain losartan's ability to bind ATR. The antiplatelet activity of DHA-L was evaluated against platelet aggregation induced by several platelet agonists. Notably, the hybrid illustrated a pleiotropic antiplatelet profile inhibiting platelet aggregation through multiple platelet activation pathways including P2Y12, PAR-1 (Protease-Activated Receptor-1), PAF (Platelet Activating Factor), COX-1 (cyclooxygenase-1) and collagen receptors. The stability of DHA-L in human plasma and in a wide range of pH values was also evaluated over time using an HPLC protocol. The hybridization approach described herein could pave the way for the development of novel potent multitargeted therapeutics with enhanced antiplatelet profile.Communicated by Ramaswamy H. Sarma.
尽管在心血管疾病 (CVDs) 的预防和治疗方面取得了科学进展，但它们仍然是全球死亡和残疾的主要原因。经典的治疗方法包括同时使用两种抗血小板药物，即阿司匹林和氯吡格雷/普拉格雷。然而，除了药物耐药性外，还表现出严重的副作用，包括急性出血和毒性。因此，具有增强疗效和减少副作用的新型治疗剂非常重要。为此，ω-3（ω-3）脂肪酸已通过抑制血小板聚集显示出对 CVDs 的有效作用，而血小板聚集在动脉血栓形成中起着关键作用。另一个在心血管疾病发病机制中起关键作用的因素是肾素-血管紧张素系统 (RAS)，特别是 ATR 阻滞剂氯沙坦，据报道，它通过该受体发挥抗血小板作用。沿着这些思路，我们设想开发一种由二十二碳六烯酸 (ω-3 脂肪酸) 和氯沙坦组成的分子杂合体，该杂合体可能对 CVDs 产生显著的抗血小板作用。设计和合成了新的 DHA-氯沙坦杂合体，命名为 DHA-L，并报告了其具有母体化合物的附加特性。首先利用研究来验证 DHA-L 保留氯沙坦与 ATR 结合能力的潜力。评估了 DHA-L 对几种血小板激动剂诱导的血小板聚集的抗血小板活性。值得注意的是，该杂合体通过包括 P2Y12、PAR-1（蛋白酶激活受体-1）、PAF（血小板激活因子）、COX-1（环氧化酶-1）和胶原受体在内的多种血小板激活途径抑制血小板聚集，显示出多效性抗血小板谱。还使用 HPLC 方案评估了 DHA-L 在人血浆中的稳定性以及在宽 pH 值范围内随时间的稳定性。本文所述的杂交方法可能为开发具有增强的抗血小板谱的新型强效多靶点治疗剂铺平道路。由 Ramaswamy H. Sarma 传达。
