TY - JOUR
T1 - Isoxazolo-[3,4-d]-pyridazin-7-(6H)-one as a potential substrate for new aldose reductase inhibitors
AU - Costantino, Luca
AU - Rastelli, Giulio
AU - Gamberini, M. Cristina
AU - Giovannoni, M. Paola
AU - Piaz, Vittorio Dal
AU - Vianello, Paola
AU - Barlocco, Daniela
PY - 1999/6/3
Y1 - 1999/6/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0033519699&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033519699&partnerID=8YFLogxK
U2 - 10.1021/jm981107o
DO - 10.1021/jm981107o
M3 - Article
C2 - 10354397
AN - SCOPUS:0033519699
VL - 42
SP - 1894
EP - 1900
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 11
ER -