About this Biochemistry, Genetics and Molecular Biology article

Synthesis and Pharmacology of Pyrido[2,3-d]pyrimidinediones Bearing Polar Substituents as Adenosine Receptor Antagonists by Jacek Bulicz; Daniela C.G. Bertarelli; Dieter Baumert; Friederike Fülle; Christa E. Müller; Dieter Heber is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

Amino-substituted pyrido[2,3-d]pyrimidinediones have previously been found to bind to adenosine A1 and A2A receptors in micromolar concentrations. The present study was aimed at studying the structure-activity relationships of this class of compounds in more detail. Most of the investigated compounds were provided with polar substituents, such as ethoxycarbonyl groups and basic amino functions, in order to improve their water-solubility. The compounds were synthesized starting from 6-amino-1,3-dimethyluracil via different reaction sequences involving (cyano)acetylation, Vilsmeier formylation, or reaction with diethyl ethoxymethylenemalonate (EMME). The most potent and selective compound of the present series was 6-carbethoxy-1,2,3,4-tetrahydro-1,3-dimethyl-5-(2-naphthylmethyl)aminopyrido[2,3-d]pyrimidine-2,4-dione (11c) with a Ki value of 5 nM at rat and 25 nM at human A1 receptors. The compound was more than 60-fold selective versus A3 and more than 300-fold selective versus A2A receptors. It showed an over 300-fold improvement with respect to the lead compound. In GTPgammaS binding studies at membranes of Chinese hamster ovary cells recombinantly expressing the human adenosine A1

Author

Jacek Bulicz; Daniela C.G. Bertarelli; Dieter Baumert; Friederike Fülle; Christa E. Müller; Dieter Heber

Publisher

Elsevier Science; Elsevier ; Elsevier Ltd.; Elsevier BV (ISSN 0968-0896)

Published

2006

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)