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diverse ARIs have been shown to substantially delay or completely prevent the onset of such
complications in experimental animal models. While some studies indicate that ALR2 may play a
functional role in osmotic homeostasis in the kidney, evidence from animal studies suggests that it is
metabolically dispensible.
Page 231
Long-term complications exact a terrible toll of morbidity and mortality on patients with diabetes
mellitus. For example, patients with diabetes have about a 25-fold increased risk for becoming blind
over that of the general population. Diabetic retinopathy is one of the most common causes of visual loss
and accounts for about 12% of new cases of blindness each year in the United States alone [5].
II. Drug Design Prior to Structural Data
Many inhibitors have been developed over the past two decades without the advantage of a structural
understanding of the enzyme [4,6,7]. Significant improvement has been made since the discovery of the
first such orally active compound to show in vivo activity, alrestatin (Figure 2), which had an IC 50 in the
low micromolar range [8]. Many high-affinity inhibitors with IC 50s in the low nanomolar range are now
under study.
Recent drug-design efforts have yielded compounds usually with one of two chemical motifs:
carboxylates or spirohydantoins. A number of these compounds such as tolrestat [9], ponalrestat [10],
epalrestat [11], sorbinil [12], and zopolrestat [13] have progressed to the point of clinical trials.
Unfortunately, clinical ineffectiveness and/or unacceptable side effects have limited the usefulness of
most of those that had been shown to be effective in vitro. The latter problems may be associated with a
lack of specificity since many aldose reductase inhibitors inhibit both ALR2 and aldehyde reductase
[14]. For this reason, ALR2 as well as the other members of the aldo-keto reductase family have been
the subject of crystallographic studies with the hope of determining a structural basis for inhibitor
specificity and ultimately to provide a basis for enhancing binding affinity.
III. Structural Studies of Aldose Reductase
The first crystal structures available for ALR2 were those of the porcine form complexed with the
NADPH analog 2'-monophosphoadenosine-5'-diphosphoribose [15] and the human enzyme complexed
with the NADPH cofactor [16]. Further studies have been conducted on mutants of the human enzyme
[17] and ternary complexes of the human enzyme with an inhibitor [18]. All of these
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