Computer-assisted design and synthesis of novel aldose reductase inhibitors.
The design and synthesis of phenalene 26 (AY-31,358), an unsubstituted analogue of a tolrestat/ICI-105,552 computer-generated hybrid (7), are reported. Compound 7 was designed by the superimposition of the putative low-energy conformers of tolrestat (1) and ICI-105,552 (6). The more rigid aldose reductase inhibitor sorbinil (2) was used as a template to help discern a common pharmacophore in the three inhibitors. Compound 26 was synthesized as a model and was evaluated as an inhibitor of bovine lens aldose reductase. It was found to exhibit good in vitro activity as well as some in vivo activity in the nerve. It was expected that introduction of the trifluoromethyl and methoxy substituents would enhance the biological activity of model compound 26. As a result of a positive Ames test with 26, however, work has now been directed toward modifying the template in a way so as to eliminate the mutagenicity with retention of biological activity.
Butera
J
J
Wyeth-Ayerst Research, Princeton, New Jersey 08543-8000.
Bagli
J
J
Doubleday
W
W
Humber
L
L
Treasurywala
A
A
Loughney
D
D
Sestanj
K
K
Millen
J
J
Sredy
J
J
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D003198:Computer Simulation; D015195:Drug Design; D007908:Lens, Crystalline / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D043803:Phenalenes; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012584:Sciatic Nerve / Q000201:enzymology; D013329:Structure-Activity Relationship; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D009281:Naphthalenes; D043803:Phenalenes; D011083:Polycyclic Compounds; D015363:Quinolones; C040550:tolrestat; C059109:2-methyl-1-oxo-1H-phenalene-3-acetic acid; C033661:ICI 105552; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase