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

Author(s):

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

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 is 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. Nevetheless, compounds 2c and 2h could represent a new chemotype to further develop inhibitors of platelet aggregation.

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

Affiliation:

Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, via Fossato di Mortara 17/19, I-44121 Ferrara, Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, via Fossato di Mortara 17/19, I-44121 Ferrara, Unità di Medicina III, Azienda Ospedaliera San Paolo, Dipartimento di Medicina Chirurgia e Odontoiatria, Università di Milano, Via di Rudinì 8, I-20142 Milano, Unità di Medicina III, Azienda Ospedaliera San Paolo, Dipartimento di Medicina Chirurgia e Odontoiatria, Università di Milano, Via di Rudinì 8, I-20142 Milano, Dipartimento di Scienze Cimiche e Farmaceutiche, Università di Trieste, Piazzale europa 1, I-34127 Trieste, Dipartimento di Scienze Cimiche e Farmaceutiche, Università di Trieste, Piazzale europa 1, I-34127 Trieste, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892 , Unità di Medicina III, Azienda Ospedaliera San Paolo, Dipartimento di Medicina Chirurgia e Odontoiatria, Università di Milano, Via di Rudinì 8, I-20142 Milano



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