Highly Selective Aldose Reductase Inhibitors. 3. Structural Diversity of 3-(Arylmethyl)-2,4,5-trioxoimidazolidine-1-acetic Acids

Abstract

Accumulation of intracellular sorbitol, the reduced product of glucose, catalyzed by aldose reductase (AR) (EC 1.1.1.21), is thought to be the cause of the development of diabetic complications. Our attention is focused on finding compounds which inhibit AR without significantly inhibiting aldehyde reductase (ALR) (EC 1.1.1.2). The uracil or 2,4-dioxoimidazolidine skeleton having the benzothiazolyl or 4-chloro-3-nitrophenyl group as an aryl part indicated not only extremely high AR inhibitory activity but also AR selectivity. The ratio of IC50(ALR)/IC50(AR) of 3-[(5-chlorobenzothiazol-2-yl)methyl]-1,2,3,4-tetrahydro-2,4- dioxopyrimidine-1-acetic acid (47d) was more than 17 500. The uracil skeleton with the benzothiazolyl moiety seemed to be the best combination for selective AR inhibition.

Merging the Binding Sites of Aldose and Aldehyde Reductase for Detection of Inhibitor Selectivity-determining Features

“…Binding of 1 to V47I is accompanied by an Table 1. Overview of selected published affinity data observed from kinetic measurements 15,16,32,[27][28][29] Ligand ALR1 (mol L −1 ) ALR2 (mol L −1 ) 1 27 10 −6 1.9 10 −8 2 N10 −4 (r) 5.7 10 −9 (r) 3 14 10 −6 30 10 −9 4 34 10 −6 a 6 10 −9 a 5 5.4 10 −6 2 10 −6 6…”

Diabetes complications and their potential prevention: Aldose reductase inhibition and other approaches

“…31 Starting from this evidence, several articles appeared reporting new compounds having, besides a carboxylic acid moiety, a benzothiazole ring. [32][33][34] All of them showed very high in vitro activity for ALR2 and selectivity with respect to aldehyde reductase (alcohol:NADP ϩ oxidoreductase, ALR1), which is also a member of the aldo-keto reductase family and shows the highest homology in structure with ALR2 (human enzyme: 65% identity). 35 Although its function is not fully understood, it has been hypothesized that ALR1 could be responsible for the reduction of many aldehydes such as 3-deoxyglucusone 36 and methylglyoxal, 37 highly reactive carbonyl compounds originating from Maillard reaction and intermediate in the formation of advanced glycation end-products (AGEs, see the following paragraphs).…”

Binding of Fidarestat Stereoisomers with Aldose Reductase

“…Excessive accumulation of intracellular sorbitol through the polyol pathway is linked to the pathogenesis of diabetic complications and prevention of sorbitol accumulation by inhibition of aldose reductase activity is an effective treatment for these complications [5][6]. A large number of structurally diverse aldose reductase inhibitors have been synthesized [7][8][9][10][11][12][13][14][15][16][17], and many molecular modeling studies have been performed to understand, on a structural basis, the interactions between inhibitors and ALR2 [18][19].…”