Target Information

Target General Infomation
Target ID
T65200
Former ID
TTDC00070
Target Name
Corticosteroid 11-beta-dehydrogenase, isozyme 1
Gene Name
HSD11B1
Synonyms
11 beta-hydroxysteroid dehydrogenase type 1; 11-DH; 11-beta-HSD1; 11-beta-hydroxysteroid dehydrogenase 1; 11HSD1; 11beta-HSD1A; 11beta-HSD2; HSD11B1
Target Type
Clinical Trial
Disease Atherosclerosis [ICD9: 414.0, 440; ICD10: I70]
Diabetes; Obesity [ICD9: 250, 278; ICD10: E08-E13, E66]
Diabetes [ICD9: 253.5, 588.1; ICD10: E23.2, N25.1]
Hypercholesterolemia [ICD10: E78]
Influenza virus [ICD10: J11.1]
Lipid metabolism disorder [ICD10: E75-E78]
Metabolic disorders [ICD9: 270-279; ICD10: E70-E89]
Metabolic syndrome x [ICD9: 277.7; ICD10: E88.81]
Non-insulin dependent diabetes [ICD10: E11.9]
Ocular hypertension [ICD9: 365.04; ICD10: H40.0]
Type 2 diabetes [ICD9: 250; ICD10: E11]
Function
Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone. Catalyzes reversibly the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. In intact cells, the reaction runs only in one direction, from 7- ketocholesterol to 7-beta-hydroxycholesterol (By similarity).
BioChemical Class
Short-chain dehydrogenases reductases
Target Validation
T65200
UniProt ID
P28845
EC Number
EC 1.1.1.146
Sequence
MAFMKKYLLPILGLFMAYYYYSANEEFRPEMLQGKKVIVTGASKGIGREMAYHLAKMGAH
VVVTARSKETLQKVVSHCLELGAASAHYIAGTMEDMTFAEQFVAQAGKLMGGLDMLILNH
ITNTSLNLFHDDIHHVRKSMEVNFLSYVVLTVAALPMLKQSNGSIVVVSSLAGKVAYPMV
AAYSASKFALDGFFSSIRKEYSVSRVNVSITLCVLGLIDTETAMKAVSGIVHMQAAPKEE
CALEIIKGGALRQEEVYYDSSLWTTLLIRNPCRKILEFLYSTSYNMDRFINK
Drugs and Mode of Action
Drug(s) GLYCYRRHIZIN Drug Info Phase 3 Influenza virus [467927], [523449]
INCB13739 Drug Info Phase 2a Type 2 diabetes [522347]
AZD-4017 Drug Info Phase 2 Ocular hypertension [523126], [542670]
BMS-770767 Drug Info Phase 2 Hypercholesterolemia [522932]
INCB13739 Drug Info Phase 2 Diabetes [522347]
JTT-654 Drug Info Phase 2 Type 2 diabetes [522824]
RG-4929 Drug Info Phase 2 Metabolic disorders [523728]
AZD8329 Drug Info Phase 1 Diabetes; Obesity [542690], [550290]
BI-135585 Drug Info Phase 1 Type 2 diabetes [523331]
BMS-816336 Drug Info Phase 1 Lipid metabolism disorder [522787]
Flavanone Drug Info Phase 1 Discovery agent [522793], [540674]
HPP-851 Drug Info Preclinical Metabolic disorders [548697]
LY-2523199 Drug Info Discontinued in Phase 2 Type 2 diabetes [549275]
AMG-221 Drug Info Discontinued in Phase 1 Metabolic disorders [547606]
PF-915275 Drug Info Discontinued in Phase 1 Non-insulin dependent diabetes [548447]
BVT-3498 Drug Info Terminated Metabolic disorders [531312]
Inhibitor (11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE Drug Info [551374]
(4-methoxyphenyl)(4-phenylazepan-1-yl)methanone Drug Info [530270]
1,1-diphenyl-3-(phenylsulfonyl)propan-2-one Drug Info [528829]
1-(1-phenyl-1H-tetrazol-5-ylthio)propan-2-one Drug Info [530901]
1-(2-adamantyl)-3-benzylpyrrolidin-2-one Drug Info [528391]
1-(3,4-dichlorophenyl)-2-(phenylsulfonyl)ethanone Drug Info [528829]
1-(3,5-dimethylphenyl)-2-(phenylsulfonyl)ethanone Drug Info [528829]
1-(3-chloropyridin-2-yl)-4-tosylpiperazine Drug Info [529500]
1-(3-methoxyphenyl)-2-(phenylsulfonyl)ethanone Drug Info [528829]
1-(3-methylpyridin-2-yl)-4-tosylpiperazine Drug Info [529500]
1-(3-nitropyridin-2-yl)-4-tosylpiperazine Drug Info [529500]
1-(4-chlorophenyl)-2-(phenylsulfonyl)ethanone Drug Info [528829]
1-(4-chlorophenylsulfonyl)-4-phenylazepan-4-ol Drug Info [530270]
1-(4-ethylphenylsulfonyl)-4-phenylazepan-4-ol Drug Info [530270]
1-(4-ethylpiperazin-1-yl)-2-phenylethanone Drug Info [528722]
1-(4-fluorophenyl)-2-(phenylsulfonyl)ethanone Drug Info [528829]
1-(4-fluorophenyl)-3-(phenylsulfonyl)propan-1-one Drug Info [528829]
1-(4-methoxyphenyl)-2-(phenylsulfonyl)ethanone Drug Info [528829]
1-(4-methoxyphenylsulfonyl)-4-phenylazepan-4-ol Drug Info [530270]
1-(4-nitrophenyl)-2-(phenylsulfonyl)ethanone Drug Info [528829]
1-(4-tert-butylphenylsulfonyl)-4-methoxyazepane Drug Info [530270]
1-(4-tert-butylphenylsulfonyl)azepan-4-ol Drug Info [530270]
1-(phenylsulfonyl)butan-2-one Drug Info [528829]
1-phenyl-2-(1-phenyl-1H-tetrazol-5-yloxy)ethanone Drug Info [530901]
1-phenyl-3-(phenylsulfonyl)propan-1-one Drug Info [528829]
1-phenyl-4-(1-phenyl-1H-tetrazol-5-yl)butan-2-one Drug Info [530901]
11-beta-HSD1 inhibitors Drug Info [543704]
11-keto-beta-boswellicacid Drug Info [530656]
11-keto-ursolic acid Drug Info [530656]
11beta-hydroxysteroid dehydrogenase-1 (HSD1) inhibitors Drug Info [543704]
2'-Monophosphoadenosine 5'-Diphosphoribose Drug Info [551393]
2-(2-chlorophenylamino)-5-methylthiazol-4(5H)-one Drug Info [529083]
2-(4-tosylpiperazin-1-yl)nicotinonitrile Drug Info [529500]
2-(adamantan-1-ylamino)-5,5-diethyl-oxazol-4-one Drug Info [528929]
2-(benzylamino)-5,5-diethyloxazol-4(5H)-one Drug Info [528929]
2-(cyclooctylamino)-5,5-diethyloxazol-4(5H)-one Drug Info [528929]
2-(N-Morpholino)-Ethanesulfonic Acid Drug Info [551393]
2-(o-toluidino)-5-ethylthiazol-4(5H)-one Drug Info [529430]
2-(o-toluidino)-5-isopropylthiazol-4(5H)-one Drug Info [529083]
2-(phenylsulfonyl)-1-(thiophen-3-yl)ethanone Drug Info [528829]
2-(phenylsulfonyl)-1-p-tolylethanone Drug Info [528829]
3-acetyl-11-keto-beta-boswellic acid Drug Info [530656]
3-acetyl-11-keto-ursolic acid Drug Info [530656]
3-benzyl-1-cyclohexylpyrrolidin-2-one Drug Info [528391]
3-epicorosolic acid methyl ester Drug Info [530656]
5,5-diethyl-2-(phenethylamino)oxazol-4(5H)-one Drug Info [528929]
5-isopropyl-2-(phenylamino)thiazol-4(5H)-one Drug Info [529083]
A-849531 Drug Info [543704]
Abietic acid Drug Info [535877]
Adamantan-1-yl-(4-ethyl-piperazin-1-yl)-methanone Drug Info [528722]
Adamantan-1-yl-piperazin-1-yl-methanone Drug Info [528722]
Adamantan-1-yl-piperidin-1-yl-methanone Drug Info [528722]
Adamantan-1-yl-pyrrolidin-1-yl-methanone Drug Info [528722]
Adamantan-2-yl-piperidin-1-yl-methanone Drug Info [528722]
AMG-221 Drug Info [530911]
AZD-4017 Drug Info [551800]
AZD8329 Drug Info [550290]
BMS-816336 Drug Info [548678]
BVT-3498 Drug Info [531312]
BVT.2733 Drug Info [535789]
Carbenoxolone Drug Info [535911], [536921], [537302]
CNX-010 Drug Info [543704]
Corosolic acid Drug Info [530656]
Enoxolone Drug Info [535911]
EQ-1280 Drug Info [543704]
FIG 1 Drug Info [529441]
Flavanone Drug Info [535877]
GLYCYRRHIZIN Drug Info [530246]
HPP-851 Drug Info [548698]
INCB13739 Drug Info [551127]
JTT-654 Drug Info [551800]
LY-2523199 Drug Info [549810]
MERCK-544 Drug Info [530715]
N-benzyl-N-(phenylsulfonyl)benzamide Drug Info [528829]
PF-877423 Drug Info [530826]
PF-915275 Drug Info [530170]
Piperidine-1-carboxylic acid adamantan-2-yl ester Drug Info [531176]
Piperidine-1-carboxylic acid adamantan-2-ylamide Drug Info [531176]
RG-4929 Drug Info [551800]
SKI-2852 Drug Info [543704]
Tormentic acid methyl ester Drug Info [530656]
URSOLIC ACID Drug Info [530656]
Modulator BI-135585 Drug Info [551800]
BMS-770767 Drug Info [551800]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Steroid hormone biosynthesis
Metabolism of xenobiotics by cytochrome P450
Metabolic pathways
Chemical carcinogenesis
NetPath Pathway IL1 Signaling Pathway
FSH Signaling Pathway
PathWhiz Pathway Steroidogenesis
Reactome Glucocorticoid biosynthesis
WikiPathways Prostaglandin Synthesis and Regulation
Metabolism of steroid hormones and vitamin D
Glucocorticoid &amp
Mineralcorticoid Metabolism
References
Ref 467927(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4688).
Ref 522347ClinicalTrials.gov (NCT00698230) Safety and Efficacy of INCB013739 Plus Metformin Compared to Metformin Alone on Glycemic Control in Type 2 Diabetics. U.S. National Institutes of Health.
Ref 522787ClinicalTrials.gov (NCT00979368) Safety Study of BMS-816336 in Healthy Male Subjects. U.S. National Institutes of Health.
Ref 522793ClinicalTrials.gov (NCT00983086) Effects of Consumption of Orange Juice on Vascular Protection and Immune Function: Clinical Study on the Specific Contribution of Citrus Flavanones. U.S. National Institutes of Health.
Ref 522824ClinicalTrials.gov (NCT00997152) Efficacy and Safety Study of JTT-654 in Type 2 Diabetic Patients. U.S. National Institutes of Health.
Ref 522932ClinicalTrials.gov (NCT01058083) Safety Study of BMS-770767 in Subjects With Hypercholesterolemia. U.S. National Institutes of Health.
Ref 523126ClinicalTrials.gov (NCT01173471) A Phase IIa Study to Assess the Tolerability, Safety, and Efficacy of AZD4017 for Raised Intra-ocular Pressure. U.S. National Institutes of Health.
Ref 523331ClinicalTrials.gov (NCT01282970) Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Oral Doses of BI 135585 XX in Patients With Type 2 Diabetes. U.S. National Institutes of Health.
Ref 523449ClinicalTrials.gov (NCT01342185) Efficacy of Medical Ozone Therapy in Patients With Chronic Hepatitis B. U.S. National Institutes of Health.
Ref 523728ClinicalTrials.gov (NCT01493271) A Study of RO5093151 in Patients With Ocular Hypertension Or Open Angle Glaucoma. U.S. National Institutes of Health.
Ref 531312Current and future drug targets in weight management. Pharm Res. 2011 Aug;28(8):1792-818.
Ref 540674(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 408).
Ref 542670(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7695).
Ref 542690(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7715).
Ref 547606Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017768)
Ref 548447Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025590)
Ref 548697Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027759)
Ref 549275Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034519)
Ref 550290Clinical pipeline report, company report or official report of AstraZeneca (2011).
Ref 528391Bioorg Med Chem Lett. 2006 Nov 1;16(21):5555-60. Epub 2006 Aug 23.Discovery of orally active butyrolactam 11beta-HSD1 inhibitors.
Ref 528722Bioorg Med Chem Lett. 2007 May 15;17(10):2838-43. Epub 2007 Feb 25.Discovery and biological evaluation of adamantyl amide 11beta-HSD1 inhibitors.
Ref 528829Bioorg 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.
Ref 528929Bioorg Med Chem Lett. 2007 Sep 1;17(17):4837-40. Epub 2007 Jun 20.Oxazolones as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1.
Ref 529083Bioorg Med Chem Lett. 2007 Nov 15;17(22):6056-61. Epub 2007 Sep 25.The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors.
Ref 529430J 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.
Ref 529441Bioorg 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.
Ref 529500Bioorg 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).
Ref 530170Bioorg 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.
Ref 530246Bioorg 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.
Ref 530270Bioorg Med Chem Lett. 2009 Aug 15;19(16):4563-5. Epub 2009 Jul 8.The discovery of azepane sulfonamides as potent 11beta-HSD1 inhibitors.
Ref 530656Bioorg 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.
Ref 530715Bioorg Med Chem Lett. 2010 Mar 1;20(5):1551-4. Epub 2010 Jan 25.Azabicyclic sulfonamides as potent 11beta-HSD1 inhibitors.
Ref 530826Bioorg Med Chem Lett. 2010 May 1;20(9):2897-902. Epub 2010 Mar 10.The development and SAR of pyrrolidine carboxamide 11beta-HSD1 inhibitors.
Ref 530901Bioorg 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.
Ref 530911J 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).
Ref 531176Bioorg Med Chem Lett. 2010 Nov 15;20(22):6725-9. Epub 2010 Sep 7.Discovery and optimization of adamantyl carbamate inhibitors of 11|A-HSD1.
Ref 531312Current and future drug targets in weight management. Pharm Res. 2011 Aug;28(8):1792-818.
Ref 535789Selective 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.
Ref 535877A 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.
Ref 535911Rapid 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.
Ref 536921Mediators of mineralocorticoid receptor-induced profibrotic inflammatory responses in the heart. Clin Sci (Lond). 2009 May;116(9):731-9.
Ref 537302Selective 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.
Ref 543704(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2763).
Ref 548678Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027626)
Ref 548698Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027759)
Ref 549810Repurposing Diabetes Drugs for Brain Insulin Resistance in Alzheimer Disease. before print June 15, 2014.
Ref 550290Clinical pipeline report, company report or official report of AstraZeneca (2011).
Ref 551127Incyte's Selective Oral Inhibitor Of 11beta-HSD1 Demonstrates Improvements In Insulin Sensitivity And Lowers Cholesterol Levels In Type 2 Diabetics. Incyte. 2008.
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 551800New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches. 2012. Chapter 5. Page(131).

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