Isoxazolo-[3,4-d]-pyridazin-7-(6H)-one as a Potential Substrate for New Aldose Reductase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 42; no. 11; pp. 1894 - 1900
• Main Authors: Costantino, Luca, Rastelli, Giulio, Gamberini, M. Cristina, Giovannoni, M. Paola, Dal Piaz, Vittorio, Vianello, Paola, Barlocco, Daniela
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 03.06.1999; Amer Chemical Soc
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - chemistry; Animals; Biological and medical sciences; Cattle; Chemistry, Medicinal; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Eye; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Lens, Crystalline - enzymology; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyridazines - chemical synthesis; Pyridazines - chemistry; Science & Technology; Structure-Activity Relationship; DIABETIC COMPLICATIONS; PROTEINS; ZOPOLRESTAT; ACIDS; Modeling; Eye; Structure activity relation; Carboxylic acid; Chlorine Organic compounds; Molecular model; Bicyclic compound; Complication; Chemical synthesis; Ungulata; Oxygen nitrogen heterocycle; Bovine; Enzyme; Diabetes mellitus; Benzene derivatives; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Vertebrata; Mammalia; Animal; Aldehyde reductase; Lens; Artiodactyla; Oxidoreductases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm981107o

The isoxazolo-[3,4-d]-pyridazin-7-(6H)-one (2) and its corresponding open derivatives 5-acetyl-4-amino-(4-nitro)-6-substituted-3(2H)pyridazinones (3, 4) were used as simplified substrates for the synthesis of new aldose reductase inhibitors with respect to the previously reported 5,6-dihydrobenzo[h]cinnolin-3(2H)one-2 acetic acids (1). Moreover, a few derivatives lacking the 5-acetyl group were prepared. Several compounds derived from 2 displayed inhibitory properties comparable to those of Sorbinil. In this class the presence at position 6 of a phenyl carrying an electron-withdrawing substituent proved to be beneficial, independently from its position on the ring (5g,j − l). Acetic acid derivatives were more effective than propionic and butyric analogues. On the contrary, all the monocyclic compounds (6 − 8) were either inactive or only weakly active. The 3-methyl-4-(p-chlorophenyl)isoxazolo-[3,4-d]-pyridazin-7-(6H)-one acetic acid (5g), which proved to be the most potent derivative, was also investigated in molecular modeling studies, to assess possible similarities in its interaction with the enzyme, with respect to the model 1.