New 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidin-5-one derivatives as diuretics.
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 Quantitative structure-activity relationships show that electron withdrawn substituents in 3-position enhance both diuretic and saliuretic activities at 25 mg/kg.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.
Monge
A
A
Department of Organic and Pharmaceutical Chemistry, Universidad de Navarra, Pamplona, Spain.
Martinez-Merino
V
V
Simon
M A
MA
Sanmartin
C
C
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004232:Diuretics / Q000138:chemical synthesis* / Q000494:pharmacology; D016018:Least-Squares Analysis; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D011188:Potassium / Q000652:urine; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012044:Regression Analysis; D013329:Structure-Activity Relationship
D004232:Diuretics; D011744:Pyrimidinones; D011188:Potassium