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Titolo/Abstract/Parole chiave

Design and Synthesis of New A2B Adenosine Receptor Antagonists

Baraldi, Stefania (2009) Design and Synthesis of New A2B Adenosine Receptor Antagonists. Tesi di Dottorato , Università degli studi di Ferrara.

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    Abstract

    Starting from chemical structure of N-benzo-[1,3]dioxol-5-yl-2-[5-(2,6dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol3-yloxy]-acetamide, MRE2029F20* various structural modifications were realized to afford a new series of A2B antagonists. The bioisosteric replacement of the anilide moiety with benzimidazole or quinazoline rings, the effect of the substitution of pyrazole with isoxazole moiety were investigated. Amide bond has been also replaced with the 5phenyl-1,2,4-oxadiazole nucleus on the basis of other adenosine pharmacophores reported previously. In this context the effect of the nitrogen at the 9-position has been also studied preparing four 9-deaza direct analogs of 8pyrazol-xanthine compounds to compare affinity and selectivity at A2B adenosine receptor. The most significant result was obtained by bioisosteric replacement of the anilide moiety with benzimidazole, achieving antagonists with high affinity and selectivity toward the A2BAR. In particular compound 8-[5-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-ylmethoxy)-2methyl-2H-pyrazol-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (hA1 Ki = 2530 nM, hA2A Ki > 1000 nM, hA2B Ki = 9.4 nM, hA3 Ki > 1000 nM) and compound 8-[5-(4,6-Bis-trifluoromethyl-1H-benzoimidazol-2-ylmethoxy)-2methyl-2H-pyrazol-3-yl]-1,3-dipropyl-3,7 dihydro-purine-2,6-dione (hA1 Ki = 4462 nM, hA2A Ki > 1000 nM, hA2B Ki = 25 nM, hA3 Ki > 1000 nM), showed the best biological data. These new selective and potent A2B antagonists will aid in the elucidation of the physiological role of this receptor and possibily lead to therapeutilally useful agents for treating asthma, diabetes and other diseases.

    Tipologia del documento:Tesi di Dottorato (Tesi di Dottorato)
    Data:23 Marzo 2009
    Relatore:Simoni, Daniele
    Coordinatore ciclo:Manfredini, Stefano
    Istituzione:Università degli studi di Ferrara
    Dottorato:XXI Anno 2006 > SCIENZE FARMACEUTICHE
    Struttura:Dipartimento > Scienze farmaceutiche
    Soggetti:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
    Depositato il:03 Lug 2009 15:00

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