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

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

Volume: 15 Issue: 8

Author(s): Barbara Cacciari*, Pamela Crepaldi, Chun Yan Cheng, Elena Bossi , Giampiero Spalluto, Stephanie Federico, Kenneth A. Jacobson and Marco Cattaneo

Affiliation:

• Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, via Fossato di Mortara 17/19, I-44121 Ferrara,Italy

Keywords: Substituted 4-amino-2-thiopyrimidine, 6-amino-2-thio-3H-pyrimin-4-one, 4-amino-2-thiopyrimidine-5-carboxylic acid, synthesis, platelet aggregation inhibition, clopidogrel.

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 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.

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.

Cite this article as:

Cacciari Barbara *, Crepaldi Pamela , Cheng Yan Chun, Bossi Elena , Spalluto Giampiero, Federico Stephanie, Jacobson A. Kenneth and Cattaneo Marco , Structure Activity Relationship of 4-Amino-2-thiopyrimidine Derivatives as Platelet Aggregation Inhibitors, Medicinal Chemistry 2019; 15 (8) . https://dx.doi.org/10.2174/1573406415666190208124534

DOI https://dx.doi.org/10.2174/1573406415666190208124534	Print ISSN 1573-4064
Publisher Name Bentham Science Publisher	Online ISSN 1875-6638