Detailed Information (TTD) -- BIDD

TTD Target ID: TTDS00115

Target Information
Name	Aldose reductase
Type of target	Successful target
Synonyms	AR
	Aldehyde reductase
Disease	Analgesics [1]
	Diabetic complications [2]
	Diabetic neuropathy [3]
	Diabetic retinopathy [4]
	Neuropathic pain [1]
	Noninsulin-dependent diabetes mellitus [5]
Drug(s)	Epalrestat		Approved	Diabetic neuropathy	[5][6]
	Sulindac		Approved	Rheumatoid arthritis	[7][8]
	Fidarestat		Phase III	Diabetes	[9][10]
	Sorbinil		Discontinued after Phase III	Diabetes	[1][11]
	Zenarestat		Discontinued	Diabetic Neuropathy	[12]
BioChemical Class	Oxidoreductases acting on the CH-OH group of donors
EC Number	EC 1.1.1.21
Pathway	Fructose and mannose metabolism
	Galactose metabolism
	Glycerolipid metabolism
	Metabolic pathways
	Pentose and glucuronate interconversions
	Pyruvate metabolism
UniProt ID	P15121
PDB Structure	1ABN; 1ADS; 1AZ1; 1AZ2; 1EF3; 1EL3; 1IEI; 1MAR.
Function	Catalyzes the nadph-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols with a broad range of catalytic efficiencies.
Sequence	MASRLLLNNGAKMPILGLGTWKSPPGQVTEAVKVAIDVGYRHIDCAHVYQNENEVGVAIQ EKLREQVVKREELFIVSKLWCTYHEKGLVKGACQKTLSDLKLDYLDLYLIHWPTGFKPGK EFFPLDESGNVVPSDTNILDTWAAMEELVDEGLVKAIGISNFNHLQVEMILNKPGLKYKP AVNQIECHPYLTQEKLIQYCQSKGIVVTAYSPLGSPDRPWAKPEDPSLLEDPRIKAIAAK HNKTTAQVLIRFPMQRNLVVIPKSVTPERIAENFKVFDFELSSQDMTTLLSYNRNWRVCA LLSCTSHKDYPFHEEF
Related US Patent	6,337,327
	6,380,200
	6,509,499
	6,555,540
	6,579,879
	6,610,890
	6,649,622
	6,670,380
Target Validation	Click to Find Target Validation Information.
QSAR Model	Click to Find Target QSAR Model.
Inhibitor	(4-Methyl-2-oxo-2H-quinolin-1-yl)-acetic acid		[13]
	(6-Hydroxy-2-oxo-2H-quinolin-1-yl)-acetic acid		[13]
	(6-Methoxy-2-oxo-2H-quinolin-1-yl)-acetic acid		[13]
	(8-Hydroxy-2-oxo-2H-quinolin-1-yl)-acetic acid		[13]
	2'-Monophosphoadenosine 5'-Diphosphoribose		[14]
	2,3-dihydroxypropanal		[15]
	2- (3,4-Dihydroxy-benzyl)-7-hydroxy-chromen-4-one		[16]
	2- (3,4-Dihydroxy-phenyl)-7-hydroxy-chromen-4-one		[16]
	2- (3-benzoyl-1H-pyrrol-1-yl)acetic acid		[17]
	2- (4-aminophenylsulfonamido)acetic acid		[18]
	2- (Phenylsulfonamido)acetic Acid		[19]
	2-Benzhydryl-7-hydroxy-chromen-4-one		[16]
	2-Benzyl-7-hydroxy-chromen-4-one		[16]
	3,5-dichlorosalicylic acid		[20]
	3- (3-Benzoyl-1H-pyrrol-1-yl)propanoic acid		[17]
	3-[5- (3-nitrophenyl)thiophen-2-yl]propanoic acid		[21]
	4- (3-Benzoyl-1H-pyrrol-1-yl)butanoic acid		[17]
	4- (3-Methoxy-phenyl)-isoxazolidine-3,5-dione		[22]
	6,7-Dihydroxy-2-phenyl-chromen-4-one		[16]
	6- (1H-Indole-2-sulfonyl)-2H-pyridazin-3-one		[23]
	6- (2-Bromo-benzenesulfonyl)-2H-pyridazin-3-one		[23]
	6- (2-Chloro-benzenesulfonyl)-2H-pyridazin-3-one		[23]
	6- (2-Fluoro-benzenesulfonyl)-2H-pyridazin-3-one		[23]
	6- (3-Chloro-benzenesulfonyl)-2H-pyridazin-3-one		[23]
	6- (4-Bromo-benzenesulfonyl)-2H-pyridazin-3-one		[23]
	6- (4-Chloro-benzenesulfonyl)-2H-pyridazin-3-one		[23]
	6- (4-Fluoro-benzenesulfonyl)-2H-pyridazin-3-one		[23]
	6- (4-Methoxy-benzenesulfonyl)-2H-pyridazin-3-one		[23]
	6- (Benzofuran-2-sulfonyl)-2H-pyridazin-3-one		[23]
	6- (Benzothiazole-2-sulfonyl)-2H-pyridazin-3-one		[23]
	6- (Biphenyl-2-sulfonyl)-2H-pyridazin-3-one		[23]
	6- (Naphthalene-1-sulfonyl)-2H-pyridazin-3-one		[23]
	6- (Naphthalene-2-sulfonyl)-2H-pyridazin-3-one		[23]
	6- (Toluene-4-sulfonyl)-2H-pyridazin-3-one		[23]
	6-Benzenesulfonyl-2H-pyridazin-3-one		[23]
	6-Hydroxy-2- (4-hydroxy-benzyl)-chromen-4-one		[16]
	6-Phenylmethanesulfonyl-2H-pyridazin-3-one		[23]
	6-methoxykaempferol 3-O-beta-D-robinobioside		[24]
	7-Hydroxy-2- (4-hydroxy-benzyl)-chromen-4-one		[16]
	7-Hydroxy-2- (4-methoxy-benzyl)-chromen-4-one		[16]
	7-Hydroxy-4-phenylcoumarin		[25]
	7-Hydroxy-6-nitro-2-phenyl-chromen-4-one		[16]
	APIGENIN		[26]
	ASTRAGALIN		[26]
	Alpha-D-Glucose-6-Phosphate		[14]
	Alrestatin		[14]
	CHRYSIN		[27]
	CONTIGOSIDE B		[28]
	DIADZEIN		[16]
	EPALRESTATE		[26]
	Epalrestat		[5][6]
	Fidarestat		[29]
	Fidarestat		[9][10]
	Fidarestat (Stereoisomer)		[14]
	Hydroxydimethylarsine Oxide		[14]
	IDD552		[14]
	IDD594		[21]
	IMIRESTAT		[30]
	Inhibitor Idd 384		[14]
	Isorhamnetin 3,7-disulfate		[28]
	KAEMPFEROL		[26]
	LIDORESTAT		[31]
	MANGIFERIN		[32]
	MINALRESTAT		[20]
N-Acetylalanine		[14]
NSC-94258		[16]
O5-Acetyl-O7-nitrooxyethyl chrysin		[27]
O7-Nitrooxyethyl chrysin		[27]
PALBINONE		[33]
Patuletin 3-O-beta-D-galactoside		[24]
Patuletin 3-O-beta-D-robinobioside		[24]
Ponalrestat		[34]
QUERCITRIN		[26]
SPR-210		[35]
Sorbinil		[29]
Sorbinil		[1][11]
Sulindac		[7][8]
TINGENIN B		[32]
TINGENONE		[32]
TRIPTOCALLINE A		[32]
Tamarixetin 3-glucoside-7-sulfate		[28]
Tolrestat		[29]
Tolrestat		[36]
ZOPOLRESTAT		[37]
Zenarestat		[12]
apigenin-7-O-beta-D-glucuronide		[26]
apigenin-7-O-beta-D-glucuronide methyl ester		[26]
isorhamnetin 3-O-rhamnoside		[38]
quercetin 3-O-neohesperidoside		[38]
Cross References	3D Structure Related Literature On-Line Medical Dictionary
Ref 1	A controlled trial of sorbinil, an aldose reductase inhibitor, in chronic painful diabetic neuropathy. Diabetes. 1983 Oct;32(10):938-42. To Reference
Ref 2	Inhibition of aldose reductase by tannoid principles of Emblica officinalis: implications for the prevention of sugar cataract. Mol Vis. 2004 Mar 12;10:148-54. To Reference
Ref 3	Aldose reductase inhibitors for the prevention and treatment of diabetic peripheral neuropathy. Cochrane Database Syst Rev. 2000;(2):CD002182. To Reference
Ref 4	The role of aldose reductase inhibitors in diabetic complications: recent trends. Methods Find Exp Clin Pharmacol. 2001 Oct;23(8):465-75. To Reference
Ref 5	Long-term effect of epalrestat, an aldose reductase inhibitor, on the development of incipient diabetic nephropathy in Type 2 diabetic patients. J Diabetes Complications. 2001 Sep-Oct;15(5):241-4. To Reference
Ref 6	Clinical investigation of epalrestat, an aldose reductase inhibitor, on diabetic neuropathy in Japan: multicenter study. Diabetic Neuropathy Study Group in Japan. J Diabetes Complications. 1996 May-Jun;10(3):168-72. To Reference
Ref 7	Biochem Pharmacol. 1983 Jul 1;32(13):1995-8.Inhibition of human lens aldose reductase by flavonoids, sulindac and indomethacin. To Reference
Ref 8	Diabetic complications in lens and nerve and their prevention by sulindac or sorbinil: two novel aldose reductase inhibitors. Invest Ophthalmol Vis Sci. 1983 Oct;24(10):1426-9. To Reference
Ref 9	Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebo-controlled double-blind parallel group study. Diabetes Care. 2001 Oct;24(10):1776-82. To Reference
Ref 10	Aldose reductase inhibitor SNK-860. Nippon Rinsho. 1997 Nov;55 Suppl:212-5. To Reference
Ref 11	Recent clinical experience with aldose reductase inhibitors. J Diabetes Complications. 1992 Jan-Mar;6(1):39-44. To Reference
Ref 12	The effects of zenarestat, an aldose reductase inhibitor, on minimal F-wave latency and nerve blood flow in streptozotocin-induced diabetic rats. Life Sci. 2001 Feb 9;68(12):1439-48. To Reference
Ref 13	J Med Chem. 1986 Oct;29(10):2024-8.Synthesis and aldose reductase inhibitory activity of substituted 2-oxoquinoline-1-acetic acid derivatives. To Reference
Ref 14	Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. To Reference
Ref 15	Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20764-9. Epub 2007 Dec 17.Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10. To Reference
Ref 16	J Med Chem. 1999 Jun 3;42(11):1881-93.1-Benzopyran-4-one antioxidants as aldose reductase inhibitors. To Reference
Ref 17	Bioorg Med Chem. 2010 Mar 15;18(6):2107-14. Epub 2010 Feb 11.Design and synthesis of novel series of pyrrole based chemotypes and their evaluation as selective aldose reductase inhibitors. A case of bioisosterism between a carboxylic acid moiety and that of a tetrazole. To Reference
Ref 18	Bioorg Med Chem. 2008 Apr 1;16(7):3926-32. Epub 2008 Jan 30.Design and synthesis of N-(3,5-difluoro-4-hydroxyphenyl)benzenesulfonamides as aldose reductase inhibitors. To Reference
Ref 19	J Med Chem. 2010 Nov 11;53(21):7756-66.A diverse series of substituted benzenesulfonamides as aldose reductase inhibitors with antioxidant activity: design, synthesis, and in vitro activity. To Reference
Ref 20	Bioorg Med Chem. 2009 Feb 1;17(3):1244-50. Epub 2008 Dec 24.Correlation of binding constants and molecular modelling of inhibitors in the active sites of aldose reductase and aldehyde reductase. To Reference
Ref 21	Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. To Reference
Ref 22	J Med Chem. 1982 Jun;25(6):745-7.Isoxazolidine-3,5-diones as lens aldose reductase inhibitors. To Reference
Ref 23	J Med Chem. 2005 Oct 6;48(20):6326-39.A novel series of non-carboxylic acid, non-hydantoin inhibitors of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-pyridazin-3-one and congeners. To Reference
Ref 24	J Nat Prod. 1984 Mar-Apr;47(2):316-9.Flavonoids with anti-cataract activity from Brickellia arguta. To Reference
Ref 25	Bioorg Med Chem Lett. 2010 Oct 1;20(19):5630-3. Epub 2010 Aug 12.6,7-Dihydroxy-4-phenylcoumarin as inhibitor of aldose reductase 2. To Reference
Ref 26	J Nat Prod. 2008 Apr;71(4):713-5. Epub 2008 Feb 26.Erigeroflavanone, a flavanone derivative from the flowers of Erigeron annuus with protein glycation and aldose reductase inhibitory activity. To Reference
Ref 27	Bioorg Med Chem. 2010 May 1;18(9):3020-5. Epub 2010 Mar 27.Synthesis, characterization and vasculoprotective effects of nitric oxide-donating derivatives of chrysin. To Reference
Ref 28	J Nat Prod. 1996 Apr;59(4):443-5.Effect of Polygonum hydropiper sulfated flavonoids on lens aldose reductase and related enzymes. To Reference
Ref 29	Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. To Reference
Ref 30	J Med Chem. 1991 Nov;34(11):3229-34.Spiro[fluoreneisothiazolidin]one dioxides: new aldose reductase and L-hexonate dehydrogenase inhibitors. To Reference
Ref 31	J Med Chem. 2005 May 5;48(9):3141-52.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. To Reference
Ref 32	J Nat Prod. 2003 Sep;66(9):1191-6.Structures of new friedelane-type triterpenes and eudesmane-type sesquiterpene and aldose reductase inhibitors from Salacia chinensis. To Reference
Ref 33	J Nat Prod. 2009 Aug;72(8):1465-70.Inhibitors of aldose reductase and formation of advanced glycation end-products in moutan cortex (Paeonia suffruticosa). To Reference
Ref 34	Ponalrestat, an aldose reductase inhibitor, inhibits cachexia syndrome induced by colon26 adenocarcinoma in mice. Anticancer Res. 1999 Sep-Oct;19(5B):4105-11. To Reference
Ref 35	Pharmacological profiles of a novel aldose reductase inhibitor, SPR-210, and its effects on streptozotocin-induced diabetic rats. Jpn J Pharmacol. 1994 Feb;64(2):115-24. To Reference
Ref 36	Aldose reductase inhibitors: an update. Ann Pharmacother. 1993 Jun;27(6):751-4. To Reference
Ref 37	Bioorg Med Chem. 2010 Apr 1;18(7):2485-90. Epub 2010 Mar 1.Chromene-3-carboxamide derivatives discovered from virtual screening as potent inhibitors of the tumour maker, AKR1B10. To Reference
Ref 38	J Nat Prod. 2002 Aug;65(8):1151-5.New flavonol oligoglycosides and polyacylated sucroses with inhibitory effects on aldose reductase and platelet aggregation from the flowers of Prunus mume. To Reference

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