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Crepaldi, Pamela (2010) SVILUPPO DI POSSIBILI NUOVI ANTAGONISTI DEL RECETTORE P2Y12. Tesi di Dottorato , Università degli Studi di Ferrara.

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    There is growing evidence that adenosine receptors could be the promising therapeutic targets in a wide range of conditions. In fact, purines and pyrimidines nucleosides and nucleotides are molecules involved in several physiological and pathophysiological processes through the activation of cell membrane receptors called purinergic receptors. These receptors are classified in P1 receptors (G-protein-coupled receptors whose natural ligand is adenosine), and P2 receptors (whose agonist and antagonist respectively are ADP and ATP)1. The P2 receptors are classified in two main groups: P2Y receptors that are G-protein linked, and P2X receptors, ligand-gated ion channels2. Among the different human P2Y subtypes, our attention was focused on the P2Y12 or P2T receptor, with a tissue distribution restricted to platelets, and subregions of the brain and vascular smooth muscle cells3. The P2Y12 receptor is a well-established target of antithrombotic drugs like ticlopidine, clopidogrel4, prasugrel and cangrelor which have proved efficacy in many clinical trials and experimental models of thrombosis. Beside the important activity as antiaggregant therapeutic candidates, P2Y12 receptors seem to be involved in the neuroprotection. They are present in high concentration in the astrocytes where they preserve the integrity of the nervous tissues5. Consequently, it’s reasonable to hypothesize an important role as therapeutic candidates in pathologies which involve a degeneration of the tissues in the some areas of the brain, such as the Huntington’s disease and the Parkinson’s disease. In order to find possible new antagonists for this receptor subtypes, we explored some 6-amino- 2-mercapto-3H-pyrimidine-4-one derivatives as extremely simplified analogs of the known ATP-congeners antagonists. In this series, the compound 1 showed a weak activity in inhibiting platelet aggregation, becoming our lead compound. Several substituents on hydroxy and thiol functions were introduced with the purpose to improve the activity (2). Some of the newly synthesized compounds showed only a slight improvement in the inhibition of platelet aggregation. The poor activity of this series of compounds could be explained with the lack of interaction with the receptor considering the very simplified utilized structure. For this reason we focused our attention on some bicyclic derivatives (3) in order to increase hydrophobic interactions into the binding site. Unfortunately and in contrast of our expectations all the derivatives of general formula 3 showed an activity comparable with the more simplified compounds (2). A possible explanation of this effect could be done considering the absence of negative charge on the core, which seems to be essential for the activity at the P2Y12 receptors as recently reported in literature6. References: 1. G. Kauffentein et al. “Adenine Triphosphate nucleotides are antagonists at P2y12 receptor” J. Thromb. Haemost. 2004, 2, 1980-1988. 2. G. Burnstock et al. “P2 purinergic receptors: modulation of cell function and therapeutic potential” J. Pharmacol. Exp. Ther. 2000, 295, 862-869. 3. I. von Kügelgen. “Pharmacological profiles of cloned-mammalian P2Y-receptors subtypes” Pharmacol. & Therapeutics. 2006, 110, 415-432. 4. P. Savi et al. “identification and biological activity of the active metabolite of clopidogrel” Thromb. Haemost. 2000, 84, 891-896. 5. L. K. Mamedova et al. “Regulation of death and survival in astrocytes by ADP activating P2Y1 and P2Y12 receptors” Biochem. Pharmacol. 2006, 72, 1031-1041. 6. Y. Baqi et al. “High- affinity, non nucleotide-derived competitive antagonists of platelet P2Y12 receptors” J. Med. Chem. 2009, 52(12), 3784-3793.

    Tipologia del documento:Tesi di Dottorato (Tesi di Dottorato)
    Data:18 Marzo 2010
    Relatore:Simoni, Daniele
    Coordinatore ciclo:Manfredini, Stefano
    Istituzione:Università degli Studi di Ferrara
    Dottorato:XXII Anno 2007 > SCIENZE FARMACEUTICHE
    Struttura:Dipartimento > Scienze farmaceutiche
    Soggetti:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
    Parole chiave:recettore P2Y12, attività antiaggregante piastrinica, tienopiridine, 6-aminotiouracile, struttura biciclica pirazolo-piramidica, P2Y12 receptor, antiaggregant activity, thienopyridine, pyrazolo-pyramidine
    Depositato il:19 Lug 2010 13:39


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