[en] Based on the recent observation that the antiplatelet agent ticagrelor and one of its metabolite exert bactericidal activity against gram-positive bacteria, a series of 1,2,3-triazolo[4,5-d]pyrimidines structurally related to ticagrelor were synthesized and examined as putative antiplatelet and antibacterial agents. The aim was to assess the possibility of dissociating the two biological properties and to find novel 1,2,3-triazolo[4,5-d]pyrimidines expressing antiplatelet activity and devoid of in vitro antibacterial activity. The new compounds synthesized were known metabolites of ticagrelor as well as structurally simplified analogues. Some of them were found to express antiplatelet activity and to lose the antibacterial activity, supporting the view that the two activities were not necessarily linked.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
Goffin, Eric ; Université de Liège - ULiège > Cardiovascular Sciences-Cardiology
Springthorpe, B., Bailey, A., Barton, P., Birkinshaw, T.N., Bonnert, R.V., Brown, R.C., Chapman, D., Dixon, J., Guile, S.D., Humphries, R.G., Hunt, S.F., Ince, F., Ingall, A.H., Kirk, I.P., Leeson, P.D., Leff, P., Lewis, R.J., Martin, B.P., McGinnity, D.F., Mortimore, M.P., Paine, S.W., Pairaudeau, G., Patel, A., Rigby, A.J., Riley, R.J., Teobald, B.J., Tomlinson, W., Webborn, P.J., Willis, P.A., From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorg. Med. Chem. Lett 17 (2007), 6013–6018.
Lutz, D.A., Hoffmann, K., Straßburger, J., Baqi, Y., Müller, C.E., von Kügelgen, I., Competitive mode and site of interaction of ticagrelor at the human platelet P2Y12-receptor. J. Thromb. Haemostasis 12 (2014), 1898–1905.
Cattaneo, M., New P2Y12 blockers. J. Thromb. Haemostasis 7:Suppl 1 (2009), 262–265.
Gurbel, P.A., Bliden, K.P., Butler, K., Antonino, M.J., Wei, C., Teng, R., Rasmussen, L., Storey, R.F., Nielsen, T., Eikelboom, J.W., Sabe-Affaki, G., Husted, S., Kereiakes, D.J., Henderson, D., Patel, D.V., Tantry, U.S., Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation 121 (2010), 1188–1199.
Teng, R., Oliver, S., Hayes, M.A., Butler, K., Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab. Dispos. 38 (2010), 1514–1521.
Lancellotti, P., Musumeci, L., Jacques, N., Servais, L., Goffin, E., Pirotte, B., Oury, C., Antibacterial activity of ticagrelor in conventional antiplatelet dosages against antibiotic-resistant Gram-positive bacteria. JAMA Cardiol 4 (2019), 596–599.
Jeong, H.S., Hong, S.J., Cho, S.A., Kim, J.H., Cho, J.Y., Lee, S.H., Joo, H.J., Park, J.H., Yu, C.W., Lim, D.S., Comparison of ticagrelor versus prasugrel for inflammation, vascular Function, and circulating endothelial progenitor cells in diabetic patients with non-ST-segment elevation acute coronary syndrome requiring coronary stenting: a prospective, randomized, crossover trial, JACC Cardiovasc. Interv 10 (2017), 1646–1658.
Gao, C.Z., Ma, Q.Q., Wu, J., Liu, R., Wang, F., Bai, J., Yang, X.J., Fu, Q., Wei, P., Comparison of the effects of ticagrelor and clopidogrel on inflammatory factors, vascular endothelium functions and short-term prognosis in patients with acute ST-segment elevation myocardial infarction undergoing emergency percutaneous coronary intervention: a pilot study. Cell. Physiol. Biochem. 48 (2018), 385–396.
Kubisa, M.J., Jezewski, M.P., Gasecka, A., Siller-Matula, J.M., Postuła, M., Ticagrelor - toward more efficient platelet inhibition and beyond. Therapeut. Clin. Risk Manag. 14 (2018), 129–140.
Fan, Q., Wang, Y., Yan, H., An NMR and DFT investigation on the interconversion of 9-substituented-N 6 -hydrazone-8-azaadenine derivatives: proton migration or conformational isomerization?. Struct. Chem. 29 (2018), 871–879.
Buchanan, A., Newton, P., Pehrsson, S., Inghardt, T., Antonsson, T., Svensson, P., Sjögren, T., Öster, L., Janefeldt, A., Sandinge, A.S., Keyes, F., Austin, M., Spooner, J., Gennemark, P., Penney, M., Howells, G., Vaughan, T., Nylander, S., Structural and functional characterization of a specific antidote for ticagrelor. Blood 125 (2015), 3484–3490.
Bojarska, J., Remko, M., Fruzinski, A., Maniukiewicz, W., The experimental and theoretical landscape of a new antiplatelet drug ticagrelor: insight into supramolecular architecture directed by C-H⋯F, π⋯π and C-H⋯π interactions. J. Mol. Struct. 1154 (2017), 290–300.
Inam, M., Wu, J., Shen, J., Phan, C.U., Tang, G., Hu, X., Preparation and characterization of novel pharmaceutical co-crystals: ticagrelor with nicotinamide. Crystals, 8, 2018, 336.
Li, Y., Landqvist, C., Grimm, S.W., Disposition and metabolism of ticagrelor, a novel P2Y12 receptor antagonist, in mice, rats, and marmosets. Drug Metab. Dispos. 39 (2011), 1555–1567.
