Monge A, Martinez-Merino V, Simon M A, Sanmartin C
Department of Organic and Pharmaceutical Chemistry, Universidad de Navarra, Pamplona, Spain.
Arzneimittelforschung. 1995 Mar;45(3):306-10.
A series of new 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e] pyrimidin-5-ones 3-substituted and/or 8,9-hydrogenated was prepared and tested for their diuretic, natriuretic and kaliuretic activities on male Wistar rats at a dosage of 25 mg/kg or less. Diuretic and saliuretic activities were strongly influenced by substituents in 3-position. Quantitative structure-activity relationships show that electron withdrawn substituents in 3-position enhance both diuretic and saliuretic activities at 25 mg/kg. Global analysis of the variations introduced on pyridine, pyrimidine and thiazole rings of this tricyclic system showed an increases of diuretic and natriuretic activities when the formal charge on N9a and C9b increases. Potassium ion excretion also increases, although not as drastically a in the earlier cases. Regression equations were calculated by partial least squares method (PLS) and validated by the cross-validation (leave-one-out) technique.
制备了一系列新的3-取代和/或8,9-氢化的5H-[1,3]噻唑并[3,2-a]吡啶并[3,2-e]嘧啶-5-酮，并以25mg/kg或更低的剂量在雄性Wistar大鼠上测试其利尿、利钠和排钾活性。3-位的取代基对利尿和利钠活性有强烈影响。定量构效关系表明，3-位的吸电子取代基在25mg/kg时可增强利尿和利钠活性。对该三环体系吡啶、嘧啶和噻唑环上引入的变化进行整体分析表明，当N9a和C9b上的形式电荷增加时，利尿和利钠活性增加。钾离子排泄也增加，尽管不像早期情况那样剧烈。通过偏最小二乘法（PLS）计算回归方程，并通过交叉验证（留一法）技术进行验证。
