Therapeutic Targets Database
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TTD Target ID: TTDC00070

Target Information
NameCorticosteroid 11-beta-dehydrogenase, isozyme 1    
Type of targetClinical trial target    
Synonyms11 beta-hydroxysteroid dehydrogenase type 1    
11-DH    
11-beta-HSD1    
11-beta-hydroxysteroid dehydrogenase 1    
11HSD1    
11beta-HSD1A    
11beta-HSD2    
DiseaseCognitive deficits (age- and dementia-associated)
[ICD9: 290-294   ICD10: F01-F07]
[1]
Diabetes Mellitus Type 2
[ICD9: 250   ICD10: E11]
[2]
Metabolic disorder, unspecified
[ICD9: 270-279   ICD10: E70-E89]
[3]
Neurodegenerative diseases
[ICD9: 330-337   ICD10: G30-G32]
[3]
Noninsulin-dependent diabetes mellitus
[ICD9: 250   ICD10: E08-E13]
[4][1][5]
Obesity
[ICD9: 278   ICD10: E66]
[6][1]
Drug(s)INCB13739Phase IIaDiabetes Mellitus Type 2[7]
BMS-770767Phase IIHypercholesterolemia
LY2409021Phase IIType 2 diabetes
LY2523199Phase IIType 2 diabetes
RG4929Phase IIType 2 diabetes
AZD4017Phase I completedDiabetes Mellitus Type 2/obesity[8]
AZD8329Phase IDiabetes, obesity[9]
BI-135585Phase IType 2 diabetes
INCB13739Phase IDiabetes Mellitus Type 1[7]
BioChemical ClassOxidoreductases acting on the CH-OH group of donors    
EC NumberEC 1.1.1.146
PathwayAndrogen and estrogen metabolism
C21-Steroid hormone metabolism
Metabolic pathways
UniProt IDP28845
PDB Structure1XU7; 1XU9; 2BEL; 2ILT; 2IRW; 2RBE; 3BYZ; 3BZU; 3CH6; 3CZR; 3D3E; 3D4N; 3D5Q; 3EY4; 3FCO; 3FRJ; 3H6K; 3HFG; 3OQ1; 3PDJ; 3QQP; 3TFQ; 4BB5; 4BB6; 4HFR; 4HX5.    
FunctionCatalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone.    
SequenceMAFMKKYLLPILGLFMAYYYYSANEEFRPEMLQGKKVIVTGASKGIGREMAYHLAKMGAH VVVTARSKETLQKVVSHCLELGAASAHYIAGTMEDMTFAEQFVAQAGKLMGGLDMLILNH ITNTSLNLFHDDIHHVRKSMEVNFLSYVVLTVAALPMLKQSNGSIVVVSSLAGKVAYPMV AAYSASKFALDGFFSSIRKEYSVSRVNVSITLCVLGLIDTETAMKAVSGIVHMQAAPKEE CALEIIKGGALRQEEVYYDSSLWTTLLIRNPCRKILEFLYSTSYNMDRFINK
Related US Patent6,730,690
Target ValidationClick to Find Target Validation Information.    
Inhibitor (11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE[10]
(4-methoxyphenyl)[11]
1,1-diphenyl-3- (phenylsulfonyl)propan-2-one[12]
1- (1-phenyl-1H-tetrazol-5-ylthio)propan-2-one[13]
1- (2-adamantyl)-3-benzylpyrrolidin-2-one[14]
1- (3,4-dichlorophenyl)-2-[12]
1- (3,5-dimethylphenyl)-2-[12]
1- (3-chloropyridin-2-yl)-4-tosylpiperazine[15]
1- (3-methoxyphenyl)-2-[12]
1- (3-methylpyridin-2-yl)-4-tosylpiperazine[15]
1- (3-nitropyridin-2-yl)-4-tosylpiperazine[15]
1- (4-chlorophenyl)-2-[12]
1- (4-chlorophenylsulfonyl)-4-phenylazepan-4-ol[11]
1- (4-ethylphenylsulfonyl)-4-phenylazepan-4-ol[11]
1- (4-ethylpiperazin-1-yl)-2-phenylethanone[16]
1- (4-fluorophenyl)-2-[12]
1- (4-fluorophenyl)-3-[12]
1- (4-methoxyphenyl)-2-[12]
1- (4-methoxyphenylsulfonyl)-4-phenylazepan-4-ol[11]
1- (4-nitrophenyl)-2-[12]
1- (4-tert-butylphenylsulfonyl)-4-methoxyazepane[11]
1- (4-tert-butylphenylsulfonyl)azepan-4-ol[11]
1- (phenylsulfonyl)butan-2-one[12]
1-phenyl-2- (1-phenyl-1H-tetrazol-5-yloxy)ethanone[13]
1-phenyl-3- (phenylsulfonyl)propan-1-one[12]
1-phenyl-4- (1-phenyl-1H-tetrazol-5-yl)butan-2-one[13]
11-keto-beta-boswellicacid[17]
11-keto-ursolic acid[17]
2'-Monophosphoadenosine 5'-Diphosphoribose[18]
2- (2-chlorophenylamino)-5-methylthiazol-4[19]
2- (4-tosylpiperazin-1-yl)nicotinonitrile[15]
2- (N-Morpholino)-Ethanesulfonic Acid[18]
2- (adamantan-1-ylamino)-5,5-diethyl-oxazol-4-one[20]
2- (benzylamino)-5,5-diethyloxazol-4[20]
2- (cyclooctylamino)-5,5-diethyloxazol-4[20]
2- (o-toluidino)-5-ethylthiazol-4[21]
2- (o-toluidino)-5-isopropylthiazol-4[19]
2- (phenylsulfonyl)-1-[12]
2- (phenylsulfonyl)-1-p-tolylethanone[12]
3-acetyl-11-keto-beta-boswellic acid[17]
3-acetyl-11-keto-ursolic acid[17]
3-benzyl-1-cyclohexylpyrrolidin-2-one[14]
3-epicorosolic acid methyl ester[17]
5,5-diethyl-2- (phenethylamino)oxazol-4[20]
5-isopropyl-2- (phenylamino)thiazol-4[19]
AMG-221[22]
AZD4017[8]
AZD8329[9]
Abietic acid[5]
BVT-14225[23]
BVT.2733[4]
Carbenoxolone[24][25][6]
Carbenoxolone[26]
Corosolic acid[17]
Enoxolone[6]
FIG 1[27]
Flavanone[5]
GLYCYRRHIZIN[28]
INCB13739[7]
MERCK-544[23]
N-benzyl-N- (phenylsulfonyl)benzamide[12]
PF-877423[29]
PF-915275[30]
Piperidine-1-carboxylic acid adamantan-2-yl ester[31]
Piperidine-1-carboxylic acid adamantan-2-ylamide[31]
Tormentic acid methyl ester[17]
URSOLIC ACID[17]
adamantan-1-yl- (4-ethyl-piperazin-1-yl)-methanone[16]
adamantan-1-yl-piperazin-1-yl-methanone[16]
adamantan-1-yl-piperidin-1-yl-methanone[16]
adamantan-1-yl-pyrrolidin-1-yl-methanone[16]
adamantan-2-yl-piperidin-1-yl-methanone[16]
glycyrrhizic acid[32]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action. Endocrinology. 2001 Apr;142(4):1371-6. To Reference
Ref 2CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008. To Reference
Ref 311beta-hydroxysteroid dehydrogenase type 1 as a novel therapeutic target in metabolic and neurodegenerative disease. Expert Opin Ther Targets. 2003 Dec;7(6):771-83. To Reference
Ref 4Selective inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains. Endocrinology. 2003 Nov;144(11):4755-62. Epub 2003 Jul 31. To Reference
Ref 5A rapid screening assay for inhibitors of 11beta-hydroxysteroid dehydrogenases (11beta-HSD): flavanone selectively inhibits 11beta-HSD1 reductase activity. Mol Cell Endocrinol. 2003 Dec 30;212(1-2):41-9. To Reference
Ref 6Rapid hepatic metabolism of 7-ketocholesterol by 11beta-hydroxysteroid dehydrogenase type 1: species-specific differences between the rat, human, and hamster enzyme. J Biol Chem. 2004 Apr 30;279(18):18415-24. Epub 2004 Feb 18. To Reference
Ref 7Incyte's Selective Oral Inhibitor Of 11beta-HSD1 Demonstrates Improvements In Insulin Sensitivity And Lowers Cholesterol Levels In Type 2 Diabetics. Incyte. 2008 To Reference
Ref 8AstraZeneca. Product Development Pipeline. January 29 2009. To Reference
Ref 92011 Pipeline of AstraZeneca. To Reference
Ref 10Berman 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 11Bioorg Med Chem Lett. 2009 Aug 15;19(16):4563-5. Epub 2009 Jul 8.The discovery of azepane sulfonamides as potent 11beta-HSD1 inhibitors. To Reference
Ref 12Bioorg Med Chem. 2007 Jul 1;15(13):4396-405. Epub 2007 Apr 25.beta-Keto sulfones as inhibitors of 11beta-hydroxysteroid dehydrogenase type I and the mechanism of action. To Reference
Ref 13Bioorg Med Chem Lett. 2010 Jun 1;20(11):3265-71. Epub 2010 Apr 18.Modulation of 11beta-hydroxysteroid dehydrogenase type 1 activity by 1,5-substituted 1H-tetrazoles. To Reference
Ref 14Bioorg Med Chem Lett. 2006 Nov 1;16(21):5555-60. Epub 2006 Aug 23.Discovery of orally active butyrolactam 11beta-HSD1 inhibitors. To Reference
Ref 15Bioorg Med Chem Lett. 2008 Jun 15;18(12):3513-6. Epub 2008 May 10.Discovery and initial SAR of arylsulfonylpiperazine inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). To Reference
Ref 16Bioorg Med Chem Lett. 2007 May 15;17(10):2838-43. Epub 2007 Feb 25.Discovery and biological evaluation of adamantyl amide 11beta-HSD1 inhibitors. To Reference
Ref 17Bioorg Med Chem. 2010 Feb 15;18(4):1507-15. Epub 2010 Jan 11.11beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational approaches. To Reference
Ref 18Overington 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 19Bioorg Med Chem Lett. 2007 Nov 15;17(22):6056-61. Epub 2007 Sep 25.The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors. To Reference
Ref 20Bioorg Med Chem Lett. 2007 Sep 1;17(17):4837-40. Epub 2007 Jun 20.Oxazolones as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1. To Reference
Ref 21J Med Chem. 2008 May 22;51(10):2933-43. Epub 2008 Apr 18.2-amino-1,3-thiazol-4(5H)-ones as potent and selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: enzyme-ligand co-crystal structure and demonstration of pharmacodynamic effects in C57Bl/6 mice. To Reference
Ref 22J Med Chem. 2010 Jun 10;53(11):4481-7.Discovery of a potent, orally active 11beta-hydroxysteroid dehydrogenase type 1 inhibitor for clinical study: identification of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221). To Reference
Ref 23Bioorg Med Chem Lett. 2010 Mar 1;20(5):1551-4. Epub 2010 Jan 25.Azabicyclic sulfonamides as potent 11beta-HSD1 inhibitors. To Reference
Ref 24Selective inhibition of 11beta-hydroxysteroid dehydrogenase 1 by 18alpha-glycyrrhetinic acid but not 18beta-glycyrrhetinic acid. J Steroid Biochem Mol Biol. 2009 Feb;113(3-5):248-52. Epub 2009 Feb 7. To Reference
Ref 25Mediators of mineralocorticoid receptor-induced profibrotic inflammatory responses in the heart. Clin Sci (Lond). 2009 May;116(9):731-9. To Reference
Ref 26Sandeep TC, Yau JL, MacLullich AM, Noble J, Deary IJ, Walker BR, Seckl JR: 11Beta-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6734-9. Epub 2004 Apr 7. To Reference
Ref 27Bioorg Med Chem Lett. 2008 Jun 1;18(11):3405-11. Epub 2008 Apr 10.4-Methyl-5-phenyl triazoles as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type I. To Reference
Ref 28Bioorg Med Chem. 2009 Aug 1;17(15):5722-32. Epub 2009 Jun 12.Discovery of novel dual functional agent as PPARgamma agonist and 11beta-HSD1 inhibitor for the treatment of diabetes. To Reference
Ref 29Bioorg Med Chem Lett. 2010 May 1;20(9):2897-902. Epub 2010 Mar 10.The development and SAR of pyrrolidine carboxamide 11beta-HSD1 inhibitors. To Reference
Ref 30Bioorg Med Chem Lett. 2009 Jul 1;19(13):3493-7. Epub 2009 May 7.N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275. To Reference
Ref 31Bioorg Med Chem Lett. 2010 Nov 15;20(22):6725-9. Epub 2010 Sep 7.Discovery and optimization of adamantyl carbamate inhibitors of 11-HSD1. To Reference
Ref 32Bioorg Med Chem Lett. 2009 Aug 1;19(15):4455-8. Epub 2009 May 15.4-(Phenylsulfonamidomethyl)benzamides as potent and selective inhibitors of the 11beta-hydroxysteroid dehydrogenase type 1 with efficacy in diabetic ob/ob mice. To Reference



 

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Professor in Department of Pharmacy
National University of Singapore, Singapore


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