(Pyrimidinyloxy)acetic acids and pyrimidineacetic acids as a novel class of aldose reductase inhibitors.
Pyrimidineacetic acids and (pyrimidinyloxy)acetic acids were synthesized by alkylation, with methyl bromoacetate or tert-butyl bromoacetate as alkylating agents. Alkylation reaction at the nitrogen or oxygen atom for different substrates was found to be solvent dependent. N-Alkylation was favored in ethereal solvent, e.g., tetrahydrofuran and dimethoxyethane, whereas O-alkylation was predominant in dimethylformamide. These compounds were tested in vitro to determine their ability to inhibit bovine lens aldose reductase. Selected compounds were assayed in vivo, in a 4-day galactose-fed rat model. The decrease in galactitol from the control was determined in lens, nerve, and diaphragm. Several of the 6-oxopyrimidine-1-acetic acids and (pyrimidinyl-4-oxy)acetic acids were found to be potent inhibitors of bovine lens aldose reductase. A study was also undertaken to determine in vitro the transport behavior of selected compounds in the isolated rat sciatic nerve. A discussion of the structure-activity relationship of this class of compounds with reference to their intrinsic biochemical activity is reported. It is concluded, in general, that ability of a compound to penetrate the tissue membrane plays an important role in the genesis of in vivo lens aldose reductase (LAR) inhibitory activity.
Ellingboe
J
J
Wyeth-Ayerst Research, Division of Exploratory Chemistry and Experimental Therapeutics, Princeton, New Jersey 08543-8000.
Alessi
T
T
Millen
J
J
Sredy
J
J
King
A
A
Prusiewicz
C
C
Guzzo
F
F
VanEngen
D
D
Bagli
J
J
D000085:Acetates; D000284:Administration, Oral; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000478:Alkylation; D000818:Animals; D002417:Cattle; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003461:Crystallography; D005693:Galactosemias / Q000188:drug therapy; D066298:In Vitro Techniques; D007908:Lens, Crystalline / Q000201:enzymology; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D000085:Acetates; D011743:Pyrimidines; D000449:Aldehyde Reductase