Structure Activity Relationship of 4-Amino-2-thiopyrimidine Derivatives as Platelet Aggregation Inhibitors

Abstract

Background: 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 COX-inhibitors, phosphodiesterase inhibitors, and thrombin inhibitors. Recently, the important role in the platelet aggregation of adenosine diphosphate (ADP)-activated P2Y12 and P2Y1 receptors, G-protein 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. Methods: 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). Results: 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. Conclusion: 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.

Extracellular Adenosine Diphosphate Stimulates CXCL10-Mediated Mast Cell Infiltration Through P2Y1 Receptor to Aggravate Airway Inflammation in Asthmatic Mice

“…According to the differential analysis of microarray GSE64913, P2Y1 was found to be differentially expressed in asthma ( Figure 1A ), and P2Y1 is also listed as P2RY1 in National Center for Biotechnology Information (NCBI). A recent study has demonstrated that ADP can activate P2Y1 ( Cacciari et al, 2019 ), while another study has suggested that P2Y1 can promote the expression of CXCL10 ( Kuboyama et al, 2011 ). To explore the mechanism of P2Y1 in asthma through CXCL10, String was used to predict the 10 genes that interacted with CXCL10 and a protein interaction network was plotted ( Figure 1B ).…”

Thio-substituted Derivatives of 4-amino-pyrazolo[3,4-d]pyrimidine-6-thiol As Antiproliferative Agents

“…The same synthetic strategy was applied to obtain the derivatives 5a-j starting from the opportune commercially available substituted pyrimidines analogs 10-13. Each compound was alkylated in the presence of NaOH in EtOH/H 2 O 50%, at 95°C for 3 hours, and opportune halide, to furnish respectively 5a-c, 5d-f, 5g-i, 5j in a good yield (roughly 50-80%) [13].…”