ArticleProceedings of the National Academy of Sciences of the United States of America1997
P1,P4-dithio-P2,P3-monochloromethylene diadenosine 5',5'''-P1,P4-tetraphosphate: a novel antiplatelet agent.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1997. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 43 citations in OpenAlex.
- Synergistic Inhibition of Both P2Y1 and P2Y12 Adenosine Diphosphate Receptors As Novel Approach to Rapidly Attenuate Platelet-Mediated Thrombosis.Arteriosclerosis, thrombosis, and vascular biology · 2016Article
- New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors.European journal of medicinal chemistry · 2016Article
- Article
- Modified diadenosine tetraphosphates with dual specificity for P2Y1 and P2Y12 are potent antagonists of ADP-induced platelet activation.Journal of thrombosis and haemostasis : JTH · 2012Article
- P1,P2-diimidazolyl derivatives of pyrophosphate and bis-phosphonates--synthesis, properties, and use in preparation of dinucleoside tetraphosphates and analogs.Organic & biomolecular chemistry · 2011Article
- Pyrimidine ribonucleotides with enhanced selectivity as P2Y(6) receptor agonists: novel 4-alkyloxyimino, (S)-methanocarba, and 5'-triphosphate gamma-ester modifications.Journal of medicinal chemistry · 2010Article
- Agonist and antagonist effects of diadenosine tetraphosphate, a platelet dense granule constituent, on platelet P2Y1, P2Y12 and P2X1 receptors.Thrombosis research · 2010Article
- One-flask synthesis of dinucleoside tetra- and pentaphosphates.Organic letters · 2006Article
- Purine and pyrimidine (P2) receptors as drug targets.Journal of medicinal chemistry · 2002Review
- Changes in extracellular pH and myocardial ischaemia alter the cardiac effects of diadenosine tetraphosphate and pentaphosphate.British journal of pharmacology · 2001Article
- The 2-5A system: modulation of viral and cellular processes through acceleration of RNA degradation.Pharmacology & therapeutics · 1998Review
- Rapid noninvasive detection of experimental atherosclerotic lesions with novel 99mTc-labeled diadenosine tetraphosphates.Proceedings of the National Academy of Sciences of the United States of America · 1998Article
- Two hydrolase resistant analogues of diadenosine 5',5"'-P1,P3-triphosphate for studies with Fhit, the human fragile histidine triad protein.Nucleosides & nucleotidesArticle
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
We have previously demonstrated in a series of searches for antithrombotic agents that diadenosine 5',5"'-P1,P4-tetraphosphate (AppppA) and its analogues are competitive inhibitors of ADP-induced platelet aggregation. Among various analogues, the P2,P3-monochloromethylene analog of AppppA (AppCHClppA) is superior to unmodified AppppA in its antiplatelet and antithrombotic effects. In this communication, we compare the antiplatelet potency of five newly synthesized agents with that of AppCHClppA. The five new agents include four diadenosine polyphosphate analogues [Ap(s)pCHClpp(s)A (p(s) indicates a thiophosphate), dAppCHClppdA, dAp,pCHClpp(s)dA, and AppCHClpCHClppA], and an adenosine tetraphosphate analogue (AppCHClpCHClp). When tested for their inhibitory effects on platelet aggregation by ADP, the most promising agent among them was Ap(s)pCHClpp(s)A. Both molecular and functional integrity of this compound proved to be stable in blood at 37 degrees C for at least 3 h. It also showed an excellent heat stability. This agent inhibits a number of aspects of ADP-induced platelet activation-e.g., release reaction, cytoplasmic calcium mobilization, thromboxane production, fibrinogen binding sites, and platelet factor 3 activity. Moreover, platelet aggregation induced by agonists other than ADP-e.g., arachidonic acid, collagen, and epinephrine-was inhibited partially by Ap(s)pCHClpp(s)A. It is concluded that (i) Ap(s)pCHClpp(s)A is a promising antiplatelet agent; (ii) it is resistant to blood phosphodiesterases and stable to heat treatment; (iii) platelet aggregation induced by collagen, epinephrine, or arachidonic acid is also inhibited in part by this agent; and (iv) specificity of the inhibitory effects is presented by unmodified adenosine moieties of the agent. Resistance to phosphodiesterases raises the possibility of oral administration.
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