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Document Figure 1 Schematic of the polyol pathway showing the NADPH-dependent reduction of open chain D-glucose to sorbitol, which is catalyzed by ALR2. This step is followed by the NAD + -dependent oxidation of sorbitol by sorbitol dehydrogenase to yield D-fructose. Page 230 significant diabetic complications. Transgenic animals overexpressing ALR2 in target tissues of diabetic complications are more prone to development of experimentally induced diabetic complications [2,3]. The most extensive body of evidence linking ALR2 to the pathogenesis of diabetic complications comes from numerous successes in the treatment of experimental animals with a variety of ALR2 inhibitors (ARI) [4]. Many of these studies demonstrated that ARIs substantially delay or in some cases prevent the onset of complications. Clinical trials of ARIs have yielded encouraging results in alleviating painful symptoms of diabetic complications. However, unacceptable side effects related to toxicity or inadequate pharmocokinetic profiles have rendered most of the drug candidates undesirable. Nevertheless, several ARIs are commercially available in some countries and more appear to be in the pipeline. The therapeutic rationale for treatment of human diabetics with ARIs to delay or prevent onset of diabetic complications is compelling. Animal models with experimentally induced hyperglycemia develop complications that are morphologically and functionally similar to that seen in the human diabetic patient. Many structurally http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_230.html (1 of 2) [4/5/2004 5:07:56 PM]
Document 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 http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_231.html [4/5/2004 5:08:00 PM]
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Document 122. Marshall WS, Beaton G
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Document dine) and didanosine (dide
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Document Page 108 mulate during tre
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Document 4 Bradykinin Receptor Anta
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Document Figure 3 Previously known
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Document References 1. Parks RE Jr.
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Document 17. Ealick SE, Rule SA, Ca
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Document Page 398 with growth hormo
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Document 17 Structure and Functiona
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Document Table 1 Approval Indicatio
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Document Page 438 proteins. One pot
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Document II. Type IFNs A great deal
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Document Page 441 sequence of the m
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Document Page 443 that allowed for
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Document Figure 4 Stereo view of IF
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Document Figure 5 Velcro-key model
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Document Figure 6 Proposed receptor
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Document Page 451 with the cytoplas
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Document Page 462 strains of influe
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Document Figure 3 (a) A MOLSCRIPT [
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Document B. Protein Structure Page
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Document Figure 5 (a) Stereo image
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Document Page 471 molecules in the
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Document Figure 8 Stereo image of t
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Document Page 476 nM, respectively.
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Document VI. Conclusion Page 480 It
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Document 21. Both GW, Sleigh MJ, Co
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Document Page 488 against most of t
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Document A. The Canyon Page 491 The
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Document Subsequent studies have sh
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Document Page 495 of the RNA and pr
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Document Figure 4 A ribbon diagram
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Document Figure 5 Some compounds wh
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Document Figure 7 HRV14 VP1 hydroph
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Document C. Structure-Activity Rela
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Document Figure 32 PTP and PTB 3D s
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Document 18. Sawyer TK. In: Peptide
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Document 97; (e) Fujii I, Nakamura
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Document Med Biol 1991; 306:9-21; (
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Document Page 629 ML, Clare M, Decr
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Document Cyclotheonamide A (CtA), 2
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document fragment-based programs, 5
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Document [Human immunodeficiency vi
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Document Kininogen, 119 high molecu
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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