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
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.