1z3n

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[[Image:1z3n.gif|left|200px]]
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{{Seed}}
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{{STRUCTURE_1z3n| PDB=1z3n | SCENE= }}
{{STRUCTURE_1z3n| PDB=1z3n | SCENE= }}
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'''Human aldose reductase in complex with NADP+ and the inhibitor lidorestat at 1.04 angstrom'''
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===Human aldose reductase in complex with NADP+ and the inhibitor lidorestat at 1.04 angstrom===
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==Overview==
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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).
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(as it appears on PubMed at http://www.pubmed.gov), where 15857120 is the PubMed ID number.
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{{ABSTRACT_PUBMED_15857120}}
==About this Structure==
==About this Structure==
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[[Category: Nadp+]]
[[Category: Nadp+]]
[[Category: Oxidoreductase]]
[[Category: Oxidoreductase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 21:59:06 2008''

Revision as of 18:59, 28 July 2008

Image:1z3n.png

Template:STRUCTURE 1z3n

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

Template:ABSTRACT PUBMED 15857120

About this Structure

1Z3N is a Single protein structure of sequence from Homo sapiens. 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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