There is significant interest in development of new antiplatelet drugs that will act directly and reversibly, avoiding clear problems with the current drug of choice, clopidogrel. Diadenosine P1,P4-tetraphosphate (Ap4A) and its phosphonate and thiophosphonate analogs such as Ap(S)pCHClpp(S)A inhibit platelet aggregation in vitro, and show antithrombotic activity in vivo, with low acute and chronic toxicity. The class has been shown to reversibly inhibit platelet ADP receptors, but the exact receptor target is not known. Existing data suggest P2Y1 targeting, but does not rule out P2Y12 inhibition as well. Bis-nucleoside polyphosphates are rapidly degraded in blood, but development of the more stable phosphonates is limited by inefficient synthesis methods that are unsuitable for large scale preparation. We have discovered a new, high yield method for synthesis of dinucleoside tetraphosphates and tetraphosphonates based on a new reagent class: stable but reactive bis-imidazolides of pyrophosphate and methylenebisphosphonates. In addition, novel boranyl derivatives of nucleoside phosphates have been described with a remarkable combination of properties, such as chemical and enzymatic stability and low toxicity, that make them useful as biological reagents and therapeutics. No boranyl derivatives of dinucleoside tetraphosphates or tetraphosphonates, however, have been described. We propose to exploit the new synthetic method to prepare selected boranyl-Ap4A analogs and, as control, the thiophosphonate Ap(S)pCHClpp(S)A, in order to study their antiplatelet activity, and to determine their antagonist/agonist properties toward P2Y1, P2Y12, and P2X1 receptors. We will also measure the stability of the new borano-Ap4A analogs in rat, dog, and human plasma. Our immediate goals are to validate and further develop our new breakthrough method for synthesis of bis-nucleoside polyphosphates, to determine if the class of Ap4A analogs targets P2Y1, or even better, both P2Y1 and P2Y12 platelet receptors, and to demonstrate the therapeutic potential and plasma stability of novel boranyl bis-nucleotide analogs. Our long range goals are to discover novel compounds and methods for treatment of arterial thrombosis, and more particularly, a fast and reversibly acting antiplatelet agent targeting platelet P2Y1, or better, both P2Y1 and P2Y12 receptors, to complement existing antiplatelet therapeutics which mainly target the platelet P2Y12 receptor. Public Health Relevance Statement This project will result in an effective antithrombotic drug that will be used to treat arterial thrombosis. The candidate drug will directly and reversibly inhibit one or both of the receptors involved in platelet aggregation, and will not have the drawbacks of slow and variable action of current drugs such as clopidogrel. The new drug will complement related drugs under development for arterial thrombosis. ? ? ?
| Chang, Hung; Yanachkov, Ivan B; Dix, Edward J et al. (2014) Antiplatelet activity, P2Y? and P2Y?? inhibition, and metabolism in plasma of stereoisomers of diadenosine 5',5'?-P¹ ,P?-dithio-P²,P³-chloromethylenetetraphosphate. PLoS One 9:e94780 |
| Chang, H; Yanachkov, I B; Dix, E J et al. (2012) Modified diadenosine tetraphosphates with dual specificity for P2Y1 and P2Y12 are potent antagonists of ADP-induced platelet activation. J Thromb Haemost 10:2573-80 |
| Yanachkov, Ivan B; Dix, Edward J; Yanachkova, Milka I et al. (2011) P1,P2-diimidazolyl derivatives of pyrophosphate and bis-phosphonates--synthesis, properties, and use in preparation of dinucleoside tetraphosphates and analogs. Org Biomol Chem 9:730-8 |
| Chang, Hung; Yanachkov, Ivan B; Michelson, Alan D et al. (2010) Agonist and antagonist effects of diadenosine tetraphosphate, a platelet dense granule constituent, on platelet P2Y1, P2Y12 and P2X1 receptors. Thromb Res 125:159-65 |
