1Z3N

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

Summary for 1Z3N

• Entry DOI: 10.2210/pdb1z3n/pdb
• Related: 1US0
• Descriptor: aldose reductase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, {3-[(4,5,7-TRIFLUORO-1,3-BENZOTHIAZOL-2-YL)METHYL]-1H-INDOL-1-YL}ACETIC ACID, ... (4 entities in total)
• Functional Keywords: oxidoreductase, nadp+, lidorestat
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 37302.39

Authors

Van Zandt, M.C.,Jones, M.L.,Gunn, D.E.,Geraci, L.S.,Jones, J.H.,Sawicki, D.R.,Sredy, J.,Jacot, J.L.,Dicioccio, A.T.,Petrova, T.,Mitschler, A.,Podjarny, A.D. (deposition date: 2005-03-14, release date: 2006-03-14, Last modification date: 2024-03-13)

Primary citation

Van Zandt, M.C.,Jones, M.L.,Gunn, D.E.,Geraci, L.S.,Jones, J.H.,Sawicki, D.R.,Sredy, J.,Jacot, J.L.,Dicioccio, A.T.,Petrova, T.,Mitschler, A.,Podjarny, A.D.
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
J.Med.Chem., 48:3141-3152, 2005

PubMed Abstract: 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).

PubMed: 15857120
DOI: 10.1021/jm0492094

Experimental method

X-RAY DIFFRACTION (1.04 Å)