Aldose reductases

Less activated substrates such as uorohaloben2enes also undergo nucleophilic displacement and thereby permit entry to other useful compounds. Bromine is preferentially displaced in -bromofluoroben2ene [460-00-4] by hydroxyl ion under the following conditions calcium hydroxide, water, cuprous oxide catalyst, 250°C, 3.46 MPa (500 psi), to give -fluorophenol [371-41-5] in 79% yield (162,163). This product is a key precursor to sorbinil, an en2yme inhibitor (aldose reductase). 

Tolrestat (28) is a long-acang aldose reductase inhibitor useful in the prophylaxis of diabetic neuropathy, retinopathy, and cataracts [24 25] Lastly, the intro-ducuon of fluorine into steroids probably ushered in the modem era of fluonnated drugs Many commercial products were introduced [2] Typical of the products are the anti inflammatory glucocorticoids dexamethasone (29 X = F, Y = H), para-methasone (29, X = H, Y = F), and flumethasone (29, X = H, Y = F)... 

Development of (Z, )-5-(2-methyl-3-phenyl-2-propenylidene)4-oxo-2-thio-xothiazolidine-3-acetic acid (Epalrestat, Kinedak), an aldose reductase inhibitor 97YGK651. 

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Oxidases/Reductases Aldose Reductase Dihydrofolate Reductase... 

Iwata Y, Arisawa M, Hamada R, Kita Y, Mizutani MY, Tomioka N, Itai A, Miyamoto S. Discovery of novel aldose reductase inhibitors using a protein structure-based approach 3D-database search followed by design and synthesis. J Med Chem 2001 44 1718-28. 

Rastelli G, Ferrari AM, Constantino L, Gamberini MC. Discovery of new inhibitors of aldose reductase from molecular docking and database screening. Bioorg Med Chem 2002 10 1437-50. 

Kramer O, Hazemann I, Podjarny AD, Klebe G. Virtual screening for inhibitors of human aldose reductase. Proteins Struct Funct Genet 2004 55 814-23. 

Kador PF The role of aldose reductase in the development of diabetic complications. Med Res Rev 1988 8 325. 

Dvornik, D. (1987). Animal models of diabetic complications and their relation to aldose reductase inhibition. In Aldose Reductase Inhibition (ed. D. Porte) pp. 153-219. McGraw-Hill, New York. 

Morikawa, T. Kishi, A. Pongpiriyadacha, Y. Matsuda, H. Yoshikawa, M. Structures of new friedelane-type triterpenes and eudesmane-type sesquiterpene and aldose reductase inhibitors from Salacia chinensis. J. Nat. Prod. 2003, 66, 1191-1196. 

Transcarbamoylase Aldose reductase Bacterial dihydrofolate reductase Phosphodiesterase... 

Aukunuru, JV, Sunkara, G, Bandi, N, Thoreson, WB, and Kompella, UB, 2001. Expression of multidrug resistance-associated protein (MRP) in human retinal pigment epithelial cells and its interaction with BAPSG, a novel aldose reductase inhibitor. Pharm Res 18, 565-572. 

Kayser, M.M., Drolet, M. and Stewart, J.D. (2005) Application of newly available bio-reducing agents to the synthesis of chiral hydroxy-beta-lactams model for aldose reductase selectivity. Tetrahedron Asymmetry, 16 (24), 4004-4009. 

---