SYNTHESIS, ACTIVITY, AND MOLECULAR MODELING OF A NEW SERIES OF TRICYCLIC PYRIDAZINONES AS SELECTIVE ALDOSE REDUCTASE INHIBITORS

Citation
L. Costantino et al., SYNTHESIS, ACTIVITY, AND MOLECULAR MODELING OF A NEW SERIES OF TRICYCLIC PYRIDAZINONES AS SELECTIVE ALDOSE REDUCTASE INHIBITORS, Journal of medicinal chemistry, 39(22), 1996, pp. 4396-4405
Citations number
53
Categorie Soggetti
Chemistry Medicinal
ISSN journal
00222623
Volume
39
Issue
22
Year of publication
1996
Pages
4396 - 4405
Database
ISI
SICI code
0022-2623(1996)39:22<4396:SAAMMO>2.0.ZU;2-A
Abstract
Three new series of tricyclic pyridazinones have been synthesized and tested in vitro in order to assess (i) their ability to inhibit aldose reductase enzyme (ALR2) and (ii) their specificity toward the target enzyme with respect to other related oxidoreductases, such as aldehyde reductase, sorbitol dehydrogenase, and glutathione reductase. The inh ibitory capability of the most effective compounds (IC50 values rangin g from 6.44 to 12.6 mu M) appears to be associated with a rather signi ficant specificity for ALR2. Molecular mechanics and molecular dynamic calculations performed on the ALR2-inhibitor complex give indications of specific interaction sites responsible for the binding, thus provi ding information for the design of new inhibitors with improved affini ty for the enzyme.