Synthesis and aldose reductase inhibitory activities of novel N-nitromethylsulfonanilide derivatives.
A novel series of 14 N-nitromethylsulfonanilide derivatives were synthesized and evaluated for their ability to inhibit recombinant aldose reductase. Computational docking simulations provided a good explanation for the observed structure-activity relationships. Kinetic analysis of (2-fluoro-5-methyl-N-methyl)-N-nitromethylsulfonanilide, 11, one of the most potent compounds in this series with an IC50 = 0.35 M, showed uncompetitive inhibition. Subsequent in vitro culture studies of rat lenses with 11 indicated that this series of aldose reductase inhibitors are effective in either preventing or retarding sugar cataract formation associated with diabetes.
Inoue
J
J
Research Laboratory, Kobe Creative Center, Senju Pharmaceutical Co., Ltd, Hyogo, Japan.
Cui
Y S
YS
Sakai
O
O
Nakamura
Y
Y
Kogiso
H
H
Kador
P F
PF
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000813:Anilides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002386:Cataract / Q000139:chemically induced / Q000188:drug therapy; D046508:Culture Techniques; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D007908:Lens, Crystalline / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014994:Xylose
C418825:(2-fluoro-5-methyl-N-methyl)-N-nitromethylsulfonanilide; D000813:Anilides; D004791:Enzyme Inhibitors; D009574:Nitro Compounds; D011994:Recombinant Proteins; D014994:Xylose; D000449:Aldehyde Reductase