Synthesis and pharmacology of pyrido[2,3-d]pyrimidinediones bearing polar substituents as adenosine receptor antagonists

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• 作者：Jacek Bulicz ; Daniela C.G. Bertarelli ; Dieter Baumert ; Friederike Fü ; lle ; Christa E. Mü ; ller and Dieter Heber
• 关键词：Adenosine receptor antagonists ; Pyrido[ ; 2 ; 3-d&#x5d ; pyrimidines ; Inverse agonist ; A₁-selectivity ; Structure&#x2013 ; activity relationships ; Gould&#x2013 ; Jacobs reaction ; Vilsmeier formylation
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2006
• 出版时间：15 April 2006
• 年：2006
• 卷：14
• 期：8
• 页码：2837-2849
• 全文大小：247 K

文摘

Amino-substituted pyrido[2,3-d]pyrimidinediones have previously been found to bind to adenosine A₁ and A_2A 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 K_i 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 A_2A receptors. It showed an over 300-fold improvement with respect to the lead compound. In GTPγS binding studies at membranes of Chinese hamster ovary cells recombinantly expressing the human adenosine A₁ receptor, 11c behaved as an antagonist with inverse agonistic activity. A regioisomer of 11c, 6-carbethoxy-1,2,3,4-tetrahydro-1,3-dimethyl-7-(2- naphthylmethyl)aminopyrido[2,3-d]pyrimidine-2,4-dione (7a) in which the 2-naphthylmethylamino substituent at position 5 of 11c was moved to the 7-position, was a relatively potent (K_i = 226 nM) and selective (>20-fold) A₃ ligand. In the series of compounds lacking an electron-withdrawing ethoxycarbonyl or cyano substituent in the 6-position, compounds with high affinity for adenosine A_2A receptors were identified, such as 1,2,3,4-tetrahydro-1,3-dimethyl-5-(1-naphthyl)aminopyrido[2,3-d]pyrimidine-2,4-dione 16b (K_i human A_2A = 81.3 nM, K_i human A₁ = 153 nM, and K_i human A₃ > 10,000 nM).