Target Information

Target General Information

Target ID

T65200 (Former ID: TTDC00070)

Target Name

Corticosteroid 11-beta-dehydrogenase 1 (HSD11B1)

Synonyms

HSD11B1; 11beta-HSD1A; 11HSD1; 11-beta-hydroxysteroid dehydrogenase 1; 11-beta-HSD1; 11-DH; 11 beta-hydroxysteroid dehydrogenase type 1

Gene Name

HSD11B1

Target Type

Clinical trial target

[1]

Disease

[+] 3 Target-related Diseases

Influenza [ICD-11: 1E30-1E32]

Lupus erythematosus [ICD-11: 4A40]

Type 2 diabetes mellitus [ICD-11: 5A11]

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.

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BioChemical Class

Short-chain dehydrogenases reductase

UniProt ID

DHI1_HUMAN

EC Number

EC 1.1.1.146

Sequence

MAFMKKYLLPILGLFMAYYYYSANEEFRPEMLQGKKVIVTGASKGIGREMAYHLAKMGAH
VVVTARSKETLQKVVSHCLELGAASAHYIAGTMEDMTFAEQFVAQAGKLMGGLDMLILNH
ITNTSLNLFHDDIHHVRKSMEVNFLSYVVLTVAALPMLKQSNGSIVVVSSLAGKVAYPMV
AAYSASKFALDGFFSSIRKEYSVSRVNVSITLCVLGLIDTETAMKAVSGIVHMQAAPKEE
CALEIIKGGALRQEEVYYDSSLWTTLLIRNPCRKILEFLYSTSYNMDRFINK

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3D Structure

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PDB

HIT2.0 ID

T40DIM

Drugs and Modes of Action

Top

Clinical Trial Drug(s)

[+] 12 Clinical Trial Drugs

BVT.2733

Drug Info

Phase 3

Lupus

[2]

GLYCYRRHIZIN

Drug Info

Phase 3

Influenza virus infection

[3], [4]

INCB13739

Drug Info

Phase 2a

Type-2 diabetes

[5]

AZD-4017

Drug Info

Phase 2

Ocular hypertension

[6], [7]

BMS-770767

Drug Info

Phase 2

Hypercholesterolaemia

[8]

JTT-654

Drug Info

Phase 2

Type-2 diabetes

[9]

RG-4929

Drug Info

Phase 2

Metabolic disorder

[10]

UE-2343

Drug Info

Phase 2

Alzheimer disease

[11], [12]

URSOLIC ACID

Drug Info

Phase 2

Metabolic syndrome x

[13]

AZD8329

Drug Info

Phase 1

Obesity

[14], [15]

BI-135585

Drug Info

Phase 1

Type-2 diabetes

[16]

BMS-816336

Drug Info

Phase 1

Lipid metabolism disorder

[17]

Discontinued Drug(s)

[+] 4 Discontinued Drugs

LY-2523199

Drug Info

Discontinued in Phase 2

Type-2 diabetes

[18]

AMG-221

Drug Info

Discontinued in Phase 1

Metabolic disorder

[19]

PF-915275

Drug Info

Discontinued in Phase 1

Non-insulin dependent diabetes

[20]

BVT-3498

Drug Info

Terminated

Metabolic disorder

[22]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

HPP-851

Drug Info

Preclinical

Metabolic disorder

[21]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 81 Inhibitor drugs

BVT.2733

Drug Info

[1]

GLYCYRRHIZIN

Drug Info

[23]

INCB13739

Drug Info

[24]

AZD-4017

Drug Info

[25]

JTT-654

Drug Info

[25]

RG-4929

Drug Info

[25]

UE-2343

Drug Info

[11], [12]

URSOLIC ACID

Drug Info

[26]

AZD8329

Drug Info

[15]

BMS-816336

Drug Info

[27]

LY-2523199

Drug Info

[28]

AMG-221

Drug Info

[29]

PF-915275

Drug Info

[30]

HPP-851

Drug Info

[31]

BVT-3498

Drug Info

[22]

(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE

Drug Info

[32]

(4-methoxyphenyl)(4-phenylazepan-1-yl)methanone

Drug Info

[33]

1,1-diphenyl-3-(phenylsulfonyl)propan-2-one

Drug Info

[34]

1-(1-phenyl-1H-tetrazol-5-ylthio)propan-2-one

Drug Info

[35]

1-(2-adamantyl)-3-benzylpyrrolidin-2-one

Drug Info

[36]

1-(3,4-dichlorophenyl)-2-(phenylsulfonyl)ethanone

Drug Info

[34]

1-(3,5-dimethylphenyl)-2-(phenylsulfonyl)ethanone

Drug Info

[34]

1-(3-chloropyridin-2-yl)-4-tosylpiperazine

Drug Info

[37]

1-(3-methoxyphenyl)-2-(phenylsulfonyl)ethanone

Drug Info

[34]

1-(3-methylpyridin-2-yl)-4-tosylpiperazine

Drug Info

[37]

1-(3-nitropyridin-2-yl)-4-tosylpiperazine

Drug Info

[37]

1-(4-chlorophenyl)-2-(phenylsulfonyl)ethanone

Drug Info

[34]

1-(4-chlorophenylsulfonyl)-4-phenylazepan-4-ol

Drug Info

[33]

1-(4-ethylphenylsulfonyl)-4-phenylazepan-4-ol

Drug Info

[33]

1-(4-ethylpiperazin-1-yl)-2-phenylethanone

Drug Info

[38]

1-(4-fluorophenyl)-2-(phenylsulfonyl)ethanone

Drug Info

[34]

1-(4-fluorophenyl)-3-(phenylsulfonyl)propan-1-one

Drug Info

[34]

1-(4-methoxyphenyl)-2-(phenylsulfonyl)ethanone

Drug Info

[34]

1-(4-methoxyphenylsulfonyl)-4-phenylazepan-4-ol

Drug Info

[33]

1-(4-nitrophenyl)-2-(phenylsulfonyl)ethanone

Drug Info

[34]

1-(4-tert-butylphenylsulfonyl)-4-methoxyazepane

Drug Info

[33]

1-(4-tert-butylphenylsulfonyl)azepan-4-ol

Drug Info

[33]

1-(phenylsulfonyl)butan-2-one

Drug Info

[34]

1-phenyl-2-(1-phenyl-1H-tetrazol-5-yloxy)ethanone

Drug Info

[35]

1-phenyl-3-(phenylsulfonyl)propan-1-one

Drug Info

[34]

1-phenyl-4-(1-phenyl-1H-tetrazol-5-yl)butan-2-one

Drug Info

[35]

11-keto-beta-boswellicacid

Drug Info

[26]

11-keto-ursolic acid

Drug Info

[26]

2'-Monophosphoadenosine 5'-Diphosphoribose

Drug Info

[39]

2-(2-chlorophenylamino)-5-methylthiazol-4(5H)-one

Drug Info

[40]

2-(4-tosylpiperazin-1-yl)nicotinonitrile

Drug Info

[37]

2-(adamantan-1-ylamino)-5,5-diethyl-oxazol-4-one

Drug Info

[41]

2-(benzylamino)-5,5-diethyloxazol-4(5H)-one

Drug Info

[41]

2-(cyclooctylamino)-5,5-diethyloxazol-4(5H)-one

Drug Info

[41]

2-(N-Morpholino)-Ethanesulfonic Acid

Drug Info

[39]

2-(o-toluidino)-5-ethylthiazol-4(5H)-one

Drug Info

[42]

2-(o-toluidino)-5-isopropylthiazol-4(5H)-one

Drug Info

[40]

2-(phenylsulfonyl)-1-(thiophen-3-yl)ethanone

Drug Info

[34]

2-(phenylsulfonyl)-1-p-tolylethanone

Drug Info

[34]

3-acetyl-11-keto-beta-boswellic acid

Drug Info

[26]

3-acetyl-11-keto-ursolic acid

Drug Info

[26]

3-benzyl-1-cyclohexylpyrrolidin-2-one

Drug Info

[36]

3-epicorosolic acid methyl ester

Drug Info

[26]

5,5-diethyl-2-(phenethylamino)oxazol-4(5H)-one

Drug Info

[41]

5-isopropyl-2-(phenylamino)thiazol-4(5H)-one

Drug Info

[40]

A-849531

Drug Info

[43]

Abietic acid

Drug Info

[44]

Adamantan-1-yl-(4-ethyl-piperazin-1-yl)-methanone

Drug Info

[38]

Adamantan-1-yl-piperazin-1-yl-methanone

Drug Info

[38]

Adamantan-1-yl-piperidin-1-yl-methanone

Drug Info

[38]

Adamantan-1-yl-pyrrolidin-1-yl-methanone

Drug Info

[38]

Adamantan-2-yl-piperidin-1-yl-methanone

Drug Info

[38]

Carbenoxolone

Drug Info

[45], [46], [47]

CNX-010

Drug Info

[43]

Corosolic acid

Drug Info

[26]

EQ-1280

Drug Info

[43]

FIG 1

Drug Info

[48]

Flavanone

Drug Info

[44]

MERCK-544

Drug Info

[49]

N-benzyl-N-(phenylsulfonyl)benzamide

Drug Info

[34]

PF-877423

Drug Info

[50]

Piperidine-1-carboxylic acid adamantan-2-yl ester

Drug Info

[51]

Piperidine-1-carboxylic acid adamantan-2-ylamide

Drug Info

[51]

SKI-2852

Drug Info

[43]

Tormentic acid methyl ester

Drug Info

[26]

[(125)I] RB129

Drug Info

[47]

Modulator

[+] 2 Modulator drugs

BMS-770767

Drug Info

[25]

BI-135585

Drug Info

[25]

Chemical Structure based Activity Landscape of Target

Top

Drug Property Profile of Target

Top

(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

Top

Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

KEGG Pathway

[+] 4 KEGG Pathways

Steroid hormone biosynthesis

Metabolism of xenobiotics by cytochrome P450

Metabolic pathways

Chemical carcinogenesis

NetPath Pathway

[+] 2 NetPath Pathways

IL1 Signaling Pathway

FSH Signaling Pathway

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Steroidogenesis

Reactome

[+] 1 Reactome Pathways

Glucocorticoid biosynthesis

WikiPathways

[+] 3 WikiPathways

Prostaglandin Synthesis and Regulation

Metabolism of steroid hormones and vitamin D

Glucocorticoid & Mineralcorticoid Metabolism

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

References

Top

REF 1

Selective inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains. Endocrinology. 2003 Nov;144(11):4755-62.

REF 2

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 3

URL: 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 4

ClinicalTrials.gov (NCT01342185) Efficacy of Medical Ozone Therapy in Patients With Chronic Hepatitis B. U.S. National Institutes of Health.

REF 5

ClinicalTrials.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 6

REF 7

ClinicalTrials.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 8

ClinicalTrials.gov (NCT01058083) Safety Study of BMS-770767 in Subjects With Hypercholesterolemia. U.S. National Institutes of Health.

REF 9

ClinicalTrials.gov (NCT00997152) Efficacy and Safety Study of JTT-654 in Type 2 Diabetic Patients. U.S. National Institutes of Health.

REF 10

ClinicalTrials.gov (NCT01493271) A Study of RO5093151 in Patients With Ocular Hypertension Or Open Angle Glaucoma. U.S. National Institutes of Health.

REF 11

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 12

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 13

ClinicalTrials.gov (NCT02337933) Effect of Ursolic Acid Administration on Insulin Sensitivity and Metabolic Syndrome. U.S. National Institutes of Health.

REF 14

REF 15

Clinical pipeline report, company report or official report of AstraZeneca (2011).

REF 16

ClinicalTrials.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 17

ClinicalTrials.gov (NCT00979368) Safety Study of BMS-816336 in Healthy Male Subjects. U.S. National Institutes of Health.

REF 18

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034519)

REF 19

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017768)

REF 20

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025590)

REF 21

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027759)

REF 22

Current and future drug targets in weight management. Pharm Res. 2011 Aug;28(8):1792-818.

REF 23

Discovery of novel dual functional agent as PPARgamma agonist and 11beta-HSD1 inhibitor for the treatment of diabetes. Bioorg Med Chem. 2009 Aug 1;17(15):5722-32.

REF 24

Incyte's Selective Oral Inhibitor Of 11beta-HSD1 Demonstrates Improvements In Insulin Sensitivity And Lowers Cholesterol Levels In Type 2 Diabetics. Incyte. 2008.

REF 25

New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches. 2012. Chapter 5. Page(131).

REF 26

11beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational a... Bioorg Med Chem. 2010 Feb 15;18(4):1507-15.

REF 27

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027626)

REF 28

Repurposing Diabetes Drugs for Brain Insulin Resistance in Alzheimer Disease. before print June 15, 2014.

REF 29

Discovery of a potent, orally active 11beta-hydroxysteroid dehydrogenase type 1 inhibitor for clinical study: identification of (S)-2-((1S,2S,4R)-b... J Med Chem. 2010 Jun 10;53(11):4481-7.

REF 30

N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275. Bioorg Med Chem Lett. 2009 Jul 1;19(13):3493-7.

REF 31

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027759)

REF 32

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 33

The discovery of azepane sulfonamides as potent 11beta-HSD1 inhibitors. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4563-5.

REF 34

beta-Keto sulfones as inhibitors of 11beta-hydroxysteroid dehydrogenase type I and the mechanism of action. Bioorg Med Chem. 2007 Jul 1;15(13):4396-405.

REF 35

Modulation of 11beta-hydroxysteroid dehydrogenase type 1 activity by 1,5-substituted 1H-tetrazoles. Bioorg Med Chem Lett. 2010 Jun 1;20(11):3265-71.

REF 36

Discovery of orally active butyrolactam 11beta-HSD1 inhibitors. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5555-60.

REF 37

Discovery and initial SAR of arylsulfonylpiperazine inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Bioorg Med Chem Lett. 2008 Jun 15;18(12):3513-6.

REF 38

Discovery and biological evaluation of adamantyl amide 11beta-HSD1 inhibitors. Bioorg Med Chem Lett. 2007 May 15;17(10):2838-43.

REF 39

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 40

The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors. Bioorg Med Chem Lett. 2007 Nov 15;17(22):6056-61.

REF 41

Oxazolones as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1. Bioorg Med Chem Lett. 2007 Sep 1;17(17):4837-40.

REF 42

2-amino-1,3-thiazol-4(5H)-ones as potent and selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: enzyme-ligand co-crystal structure an... J Med Chem. 2008 May 22;51(10):2933-43.

REF 43

REF 44

A 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 45

Selective 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.

REF 46

Mediators of mineralocorticoid receptor-induced profibrotic inflammatory responses in the heart. Clin Sci (Lond). 2009 May;116(9):731-9.

REF 47

Rapid hepatic metabolism of 7-ketocholesterol by 11beta-hydroxysteroid dehydrogenase type 1: species-specific differences between the rat, human, a... J Biol Chem. 2004 Apr 30;279(18):18415-24.

REF 48

4-Methyl-5-phenyl triazoles as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type I. Bioorg Med Chem Lett. 2008 Jun 1;18(11):3405-11.

REF 49

Azabicyclic sulfonamides as potent 11beta-HSD1 inhibitors. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1551-4.

REF 50

The development and SAR of pyrrolidine carboxamide 11beta-HSD1 inhibitors. Bioorg Med Chem Lett. 2010 May 1;20(9):2897-902.

REF 51

Discovery and optimization of adamantyl carbamate inhibitors of 11-HSD1. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6725-9.

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