1z3n

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spinqualitylabelsall models 1z3n, resolution 1.04Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Human aldose reductase in complex with NADP+ and the inhibitor lidorestat at 1.04 angstrom

Overview

Recent efforts to identify treatments for chronic diabetic complications, have resulted in the discovery of a novel series of highly potent and, selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose, reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid, (lidorestat, 9) inhibits aldose reductase with an IC(50) of 5 nM, while, being 5400 times less active against aldehyde reductase, a related enzyme, involved in the detoxification of reactive aldehydes. It lowers nerve and, lens sorbitol levels with ED(50)'s of 1.9 and 4.5 mg/kg/d po, respectively, in the 5-day STZ-induced diabetic rat model. In a 3-month, diabetic intervention model (1 month of diabetes followed by 2 months of, drug treatment at 5 mg/kg/d po), it normalizes polyols and reduces the, motor nerve conduction velocity deficit by 59% relative to diabetic, controls. It has a favorable pharmacokinetic profile (F, 82%; t(1/2), 5.6, h; Vd, 0.694 L/kg) with good drug penetration in target tissues (C(max) in, sciatic nerve and eye are 2.36 and 1.45 mug equiv/g, respectively, when, dosed with [(14)C]lidorestat at 10 mg/kg po).

About this Structure

1Z3N is a Single protein structure of sequence from Homo sapiens with NDP and 3NA as ligands. Active as Aldehyde reductase, with EC number 1.1.1.21 Full crystallographic information is available from OCA.

Reference

Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications., Van Zandt MC, Jones ML, Gunn DE, Geraci LS, Jones JH, Sawicki DR, Sredy J, Jacot JL, Dicioccio AT, Petrova T, Mitschler A, Podjarny AD, J Med Chem. 2005 May 5;48(9):3141-52. PMID:15857120

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