Dorigo P, Fraccarollo D, Santostasi G, Maragno I, Floreani M, Borea P A, Mosti L, Sansebastiano L, Fossa P, Orsini F, Benetollo F, Bombieri G
Dipartimento di Farmacologia, Università di Padova, Italy.
J Med Chem. 1996 Sep 13;39(19):3671-83. doi: 10.1021/jm9508649.
The synthesis of ethyl or methyl 4-substituted or unsubstituted 2-(dimethylamino)-5-pyrimidinecarboxylates 10-20, which is mainly carried out by reaction of ethyl or methyl 2-[(dimethylamino)methylene]-3-oxoalkanoates with 1,1-dimethylguanidine, is described. The above esters were hydrolyzed to the relative carboxylic acids 21-30, which were decarboxylated to the corresponding 2,4-disubstituted pyrimidines 31-40. All the new synthesized pyrimidines were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Their effects were compared to those induced by milrinone in both atria preparations. Compound 28 (4-benzyl-2-(dimethylamino)-5-pyrimidinecarboxylic acid) was the most effective positive inotropic agent, while the corresponding methyl ester 17 reduced both the contractile force and the frequency of guinea pig atria. An antagonism toward the negative influence exerted by endogenous adenosine on the heart seems to be involved in the contractile activity of compound 28. By contrast, compound 17 might be partial agonist at the purinergic inhibitory (A1) receptor. X-ray analysis carried out on 17 and 28 and molecular modeling investigations extended also to related derivatives allowed a possible rationalization between structure and inotropic activity for this series of compounds.
描述了4-取代或未取代的2-(二甲基氨基)-5-嘧啶羧酸乙酯或甲酯10-20的合成，其主要通过2-[(二甲基氨基)亚甲基]-3-氧代链烷酸乙酯或甲酯与1,1-二甲基胍反应进行。上述酯被水解为相应的羧酸21-30，后者脱羧得到相应的2,4-二取代嘧啶31-40。所有新合成的嘧啶在利血平处理的豚鼠的自发搏动和电驱动心房中进行了评估。在两种心房制剂中，将它们的作用与米力农诱导的作用进行了比较。化合物28（4-苄基-2-(二甲基氨基)-5-嘧啶羧酸）是最有效的正性肌力药物，而相应的甲酯17降低了豚鼠心房的收缩力和频率。化合物28的收缩活性似乎涉及对内源性腺苷对心脏施加的负面影响的拮抗作用。相比之下，化合物17可能是嘌呤能抑制（A1）受体的部分激动剂。对17和28进行的X射线分析以及扩展到相关衍生物的分子模拟研究使得对该系列化合物的结构与正性肌力活性之间的关系进行合理推测成为可能。
