Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, via Fossato di Mortara 17/19, I-44121 Ferrara, Italy.
Unità di Medicina III, Azienda Ospedaliera San Paolo, Dipartimento di Scienze della Salute, Università di Milano, Via di Rudinì 8, I-20142 Milano, Italy.
Med Chem. 2019;15(8):863-872. doi: 10.2174/1573406415666190208124534.
Platelet aggregation plays a pathogenic role in the development of arterial thrombi, which are responsible for common diseases caused by thrombotic arterial occlusion, such as myocardial infarction and stroke. Much efforts are directed toward developing platelet aggregation inhibitors that act through several mechanisms: The main antiplatelet family of COXinhibitors, phosphodiesterase inhibitors, and thrombin inhibitors. Recently, the important role in the platelet aggregation of adenosine diphosphate (ADP)-activated P2Y12 and P2Y1 receptors, Gprotein coupled receptors of the P2 purinergic family, has emerged, and their inhibitors are explored as potential therapeutic antithrombotics. P2Y12 inhibitors, i.e. clopidogrel, prasugrel, ticagrelor, and cangrelor, are already used clinically to reduce coronary artery thrombosis risk and prevent acute coronary syndromes. The search for new P2Y12 inhibitors, with better risk-to-benefit profiles is still ongoing.
Several years ago, our group prepared a series of 6-amino-2-thio-3H-pyrimidin-4-one derivatives that displayed an interesting platelet aggregation inhibiting activity. In order to probe the structure-activity relationships and improve their inhibitory effects of these compounds, we synthesized variously substituted 6-amino-2-thio-3H-pyrimidin-4-one derivatives and substituted 4-amino-2-thiopyrimidine-5-carboxylic acid analogues. All the synthesized compounds were tested by light trasmission aggregometry (LTA) as inducers or inhibitors of platelet aggregation in citrated platelet-rich plasma (PRP).
Among the 6-amino-2-thio-3H-pyrimidin-4-one derivatives, compounds 2c and 2h displayed marked inhibitory activity, with a capability to inhibit the ADP(10-6M)-induced platelet aggregation by 91% and 87% at 10-4M concentration, respectively. Selected 4-amino-2- thiopyrimidine-5-carboxylic acid derivatives were tested as P2Y12 and P2Y1 antagonists and found to display negligible activity.
These negative findings demonstrated that this heterocyclic nucleus is not a useful common pharmacophore for developing P2Y-dependent inhibitors of platelet aggregation. Nevertheless, compounds 2c and 2h could represent a new chemotype to further develop inhibitors of platelet aggregation.
血小板聚集在动脉血栓形成的发病机制中起作用，动脉血栓负责由血栓性动脉闭塞引起的常见疾病，如心肌梗死和中风。人们致力于开发通过几种机制起作用的血小板聚集抑制剂：COX 抑制剂、磷酸二酯酶抑制剂和凝血酶抑制剂的主要抗血小板家族。最近，在血小板聚集中，二磷酸腺苷 (ADP) 激活的 P2Y12 和 P2Y1 受体、P2 嘌呤能家族的 G 蛋白偶联受体的重要作用已经显现出来，并且它们的抑制剂被探索为潜在的治疗性抗血栓药。P2Y12 抑制剂，即氯吡格雷、普拉格雷、替卡格雷和坎格雷洛，已在临床上用于降低冠状动脉血栓形成风险和预防急性冠状动脉综合征。寻找具有更好风险效益比的新型 P2Y12 抑制剂仍在进行中。
几年前，我们小组制备了一系列 6-氨基-2-硫代-3H-嘧啶-4-酮衍生物，这些衍生物表现出有趣的血小板聚集抑制活性。为了探究这些化合物的构效关系并提高其抑制作用，我们合成了各种取代的 6-氨基-2-硫代-3H-嘧啶-4-酮衍生物和取代的 4-氨基-2-硫代嘧啶-5-羧酸类似物。所有合成的化合物均通过光透射聚集测定法 (LTA) 作为诱导物或抑制剂在柠檬酸盐富血小板血浆 (PRP) 中检测血小板聚集。
在 6-氨基-2-硫代-3H-嘧啶-4-酮衍生物中，化合物 2c 和 2h 表现出显著的抑制活性，在 10-4M 浓度下分别能够抑制 ADP(10-6M)诱导的血小板聚集 91%和 87%。选定的 4-氨基-2-硫代嘧啶-5-羧酸衍生物作为 P2Y12 和 P2Y1 拮抗剂进行测试，发现其活性可忽略不计。
这些阴性结果表明，这个杂环核不是开发依赖于 P2Y 的血小板聚集抑制剂的有用共同药效团。然而，化合物 2c 和 2h 可能代表进一步开发血小板聚集抑制剂的新化学型。
