Anticataract activity of analogs of a sorbitol dehydrogenase inhibitor.
The initiation of sugar cataract formation by the aldose reductase catalyzed accumulation of sorbitol in diabetic rats, and its prevention by the administration of aldose reductase inhibitors at the onset or early stages of diabetes, has been well established. In contrast, the inhibition of sorbitol dehydrogenase by 4-[4-(N,N-dimethylsulfamoyl)piperazino]-2-hydroxymethylpyrimidine (SDI-1) has been observed to increase the onset in severity of sugar cataract formation in diabetic rats. Two analogs of SDI-1 have been synthesized, where the 4-(2-hydroxymethyl)pyrimidine ring has been replaced with either a 4-(2,6-dimethoxy)-pyrimidine ring or a 2-pyrimidine ring. Neither compound, 2-[4-(N,N-dimethylsulfamoyl)piperazino]-pyrimidine (SRA-1) or 4-[4-(N,N-dimethylsulfamoyl) piperazino]-2,6-dimethoxypyrimidine (SRA-2), demonstrated significant sorbitol dehydrogenase or aldose reductase inhibition. Oral administration of these compounds to streptozotocin diabetic rats, however, delayed cataract formation without reducing the levels of hyperglycemia or lens polyol.
Kador
Peter F
PF
College of Pharmacy, University of Nebraska Medical Center, Omaha, NE., USA. pkador@unmc.edu
Inoue
Jun
J
Blessing
Karen
K
D000818:Animals; D002386:Cataract / Q000188:drug therapy* / Q000201:enzymology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; C092078:S 0773; C106112:2-hydroxymethyl-4-(4-(N,N-dimethylaminosulfonyl)-1-piperazino)pyrimidine; D007064:L-Iditol 2-Dehydrogenase