Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTN7BL9)

• DTT 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
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Short-chain dehydrogenases reductase
• UniProt ID: DHI1_HUMAN
• TTD ID: T65200
• EC Number: EC 1.1.1.146
• Sequence:
  MAFMKKYLLPILGLFMAYYYYSANEEFRPEMLQGKKVIVTGASKGIGREMAYHLAKMGAH
  VVVTARSKETLQKVVSHCLELGAASAHYIAGTMEDMTFAEQFVAQAGKLMGGLDMLILNH
  ITNTSLNLFHDDIHHVRKSMEVNFLSYVVLTVAALPMLKQSNGSIVVVSSLAGKVAYPMV
  AAYSASKFALDGFFSSIRKEYSVSRVNVSITLCVLGLIDTETAMKAVSGIVHMQAAPKEE
  CALEIIKGGALRQEEVYYDSSLWTTLLIRNPCRKILEFLYSTSYNMDRFINK
• 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.
• KEGG Pathway:
  Steroid hormone biosynthesis (hsa00140)
  Metabolism of xenobiotics by cytochrome P450 (hsa00980)
  Metabolic pathways (hsa01100)
  Chemical carcinogenesis (hsa05204)
• Reactome Pathway: Glucocorticoid biosynthesis (R-HSA-194002)
• BioCyc Pathway: MetaCyc:HS04154-MON

Molecular Interaction Atlas (MIA) of This DTT

13 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BVT.2733	DM6RUKX	Lupus	4A40	Phase 3	[1]
GLYCYRRHIZIN	DM8M2N3	Influenza virus infection	1E30-1E32	Phase 3	[2]
INCB13739	DMLQ3PO	Type-2 diabetes	5A11	Phase 2a	[3]
AZD-4017	DML9M5S	Ocular hypertension	9C61.01	Phase 2	[4]
BMS-770767	DMTVGY7	Hypercholesterolaemia	5C80.0	Phase 2	[4]
JTT-654	DM50M2R	Type-2 diabetes	5A11	Phase 2	[4]
RG-4929	DMT4QRD	Metabolic disorder	5C50-5D2Z	Phase 2	[4]
UE-2343	DMIERPK	Alzheimer disease	8A20	Phase 2	[5]
URSOLIC ACID	DM4SOAW	Metabolic syndrome x	5C50-5D2Z	Phase 2	[6]
Xanamem	DM580GT	Alzheimer disease	8A20	Phase 1/2	[7]
AZD8329	DMTD57A	Diabetic complication	5A2Y	Phase 1	[8]
BI-135585	DMLJOAF	Type-2 diabetes	5A11	Phase 1	[4]
BMS-816336	DM2WMJ7	Lipid metabolism disorder	5C52.Z	Phase 1	[9]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LY-2523199	DMGE9OA	Type-2 diabetes	5A11	Discontinued in Phase 2	[10]
AMG-221	DMFCKJ1	Metabolic disorder	5C50-5D2Z	Discontinued in Phase 1	[11]
PF-915275	DMB7EIN	Non-insulin dependent diabetes	5A11	Discontinued in Phase 1	[12]
BVT-3498	DMOZQHX	Metabolic disorder	5C50-5D2Z	Terminated	[14]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
HPP-851	DM69UZG	Metabolic disorder	5C50-5D2Z	Preclinical	[13]

66 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE	DMTPQ84	Discovery agent	N.A.	Investigative	[15]
(4-methoxyphenyl)(4-phenylazepan-1-yl)methanone	DMZD0KG	Discovery agent	N.A.	Investigative	[16]
1,1-diphenyl-3-(phenylsulfonyl)propan-2-one	DM7SQ4H	Discovery agent	N.A.	Investigative	[17]
1-(1-phenyl-1H-tetrazol-5-ylthio)propan-2-one	DMSUC85	Discovery agent	N.A.	Investigative	[18]
1-(2-adamantyl)-3-benzylpyrrolidin-2-one	DMRHY2M	Discovery agent	N.A.	Investigative	[19]
1-(3,4-dichlorophenyl)-2-(phenylsulfonyl)ethanone	DM4YWEL	Discovery agent	N.A.	Investigative	[17]
1-(3,5-dimethylphenyl)-2-(phenylsulfonyl)ethanone	DMYJ4EG	Discovery agent	N.A.	Investigative	[17]
1-(3-chloropyridin-2-yl)-4-tosylpiperazine	DM6LWR2	Discovery agent	N.A.	Investigative	[20]
1-(3-methoxyphenyl)-2-(phenylsulfonyl)ethanone	DMR0ICB	Discovery agent	N.A.	Investigative	[17]
1-(3-methylpyridin-2-yl)-4-tosylpiperazine	DMYH9M0	Discovery agent	N.A.	Investigative	[20]
1-(3-nitropyridin-2-yl)-4-tosylpiperazine	DM3FP6J	Discovery agent	N.A.	Investigative	[20]
1-(4-chlorophenyl)-2-(phenylsulfonyl)ethanone	DMQHTR4	Discovery agent	N.A.	Investigative	[17]
1-(4-chlorophenylsulfonyl)-4-phenylazepan-4-ol	DMEJXWG	Discovery agent	N.A.	Investigative	[16]
1-(4-ethylphenylsulfonyl)-4-phenylazepan-4-ol	DMXUIS2	Discovery agent	N.A.	Investigative	[16]
1-(4-ethylpiperazin-1-yl)-2-phenylethanone	DMRK0Z1	Discovery agent	N.A.	Investigative	[21]
1-(4-fluorophenyl)-2-(phenylsulfonyl)ethanone	DMZLNAP	Discovery agent	N.A.	Investigative	[17]
1-(4-fluorophenyl)-3-(phenylsulfonyl)propan-1-one	DMKATOJ	Discovery agent	N.A.	Investigative	[17]
1-(4-methoxyphenyl)-2-(phenylsulfonyl)ethanone	DMRC7V8	Discovery agent	N.A.	Investigative	[17]
1-(4-methoxyphenylsulfonyl)-4-phenylazepan-4-ol	DMG7PKA	Discovery agent	N.A.	Investigative	[16]
1-(4-nitrophenyl)-2-(phenylsulfonyl)ethanone	DM1M67Q	Discovery agent	N.A.	Investigative	[17]
1-(4-tert-butylphenylsulfonyl)-4-methoxyazepane	DMM7IJZ	Discovery agent	N.A.	Investigative	[16]
1-(4-tert-butylphenylsulfonyl)azepan-4-ol	DMQECWT	Discovery agent	N.A.	Investigative	[16]
1-(phenylsulfonyl)butan-2-one	DMRGD8W	Discovery agent	N.A.	Investigative	[17]
1-phenyl-2-(1-phenyl-1H-tetrazol-5-yloxy)ethanone	DMZM9AI	Discovery agent	N.A.	Investigative	[18]
1-phenyl-3-(phenylsulfonyl)propan-1-one	DM8ZBHF	Discovery agent	N.A.	Investigative	[17]
1-phenyl-4-(1-phenyl-1H-tetrazol-5-yl)butan-2-one	DMKV17L	Discovery agent	N.A.	Investigative	[18]
11-keto-beta-boswellicacid	DMM6CJI	Discovery agent	N.A.	Investigative	[6]
11-keto-ursolic acid	DM1WPE3	Discovery agent	N.A.	Investigative	[6]
2'-Monophosphoadenosine 5'-Diphosphoribose	DME9S8M	Discovery agent	N.A.	Investigative	[22]
2-(2-chlorophenylamino)-5-methylthiazol-4(5H)-one	DMJ38LE	Discovery agent	N.A.	Investigative	[23]
2-(4-tosylpiperazin-1-yl)nicotinonitrile	DMED9FL	Discovery agent	N.A.	Investigative	[20]
2-(adamantan-1-ylamino)-5,5-diethyl-oxazol-4-one	DMB3YXG	Discovery agent	N.A.	Investigative	[24]
2-(benzylamino)-5,5-diethyloxazol-4(5H)-one	DMW27AC	Discovery agent	N.A.	Investigative	[24]
2-(cyclooctylamino)-5,5-diethyloxazol-4(5H)-one	DMAPW5K	Discovery agent	N.A.	Investigative	[24]
2-(N-Morpholino)-Ethanesulfonic Acid	DMZVHSB	Discovery agent	N.A.	Investigative	[22]
2-(o-toluidino)-5-ethylthiazol-4(5H)-one	DM3RCA9	Discovery agent	N.A.	Investigative	[25]
2-(o-toluidino)-5-isopropylthiazol-4(5H)-one	DMYTJX4	Discovery agent	N.A.	Investigative	[23]
2-(phenylsulfonyl)-1-(thiophen-3-yl)ethanone	DMCF75U	Discovery agent	N.A.	Investigative	[17]
2-(phenylsulfonyl)-1-p-tolylethanone	DM93XJT	Discovery agent	N.A.	Investigative	[17]
3-acetyl-11-keto-beta-boswellic acid	DMGO2D7	Discovery agent	N.A.	Investigative	[6]
3-acetyl-11-keto-ursolic acid	DMHRZ2V	Discovery agent	N.A.	Investigative	[6]
3-benzyl-1-cyclohexylpyrrolidin-2-one	DMNG0TY	Discovery agent	N.A.	Investigative	[19]
3-epicorosolic acid methyl ester	DMQ8VIU	Discovery agent	N.A.	Investigative	[6]
5,5-diethyl-2-(phenethylamino)oxazol-4(5H)-one	DMWL1UY	Discovery agent	N.A.	Investigative	[24]
5-isopropyl-2-(phenylamino)thiazol-4(5H)-one	DM2TNWO	Discovery agent	N.A.	Investigative	[23]
A-849531	DMJBPR3	Metabolic disorder	5C50-5D2Z	Investigative	[26]
Abietic acid	DMW1Y2G	Discovery agent	N.A.	Investigative	[27]
Adamantan-1-yl-(4-ethyl-piperazin-1-yl)-methanone	DM4S279	Discovery agent	N.A.	Investigative	[21]
Adamantan-1-yl-piperazin-1-yl-methanone	DM5K0EI	Discovery agent	N.A.	Investigative	[21]
Adamantan-1-yl-piperidin-1-yl-methanone	DMTUL9J	Discovery agent	N.A.	Investigative	[21]
Adamantan-1-yl-pyrrolidin-1-yl-methanone	DMAEN9Y	Discovery agent	N.A.	Investigative	[21]
Adamantan-2-yl-piperidin-1-yl-methanone	DMBRAV5	Discovery agent	N.A.	Investigative	[21]
Carbenoxolone	DMO648T	Discovery agent	N.A.	Investigative	[28]
CNX-010	DMDK5BL	Non-insulin dependent diabetes	5A11	Investigative	[26]
Corosolic acid	DM563PZ	Discovery agent	N.A.	Investigative	[6]
EQ-1280	DM2KMNU	Diabetic complication	5A2Y	Investigative	[26]
FIG 1	DM29TVC	Discovery agent	N.A.	Investigative	[29]
Flavanone	DMNWIYM	Discovery agent	N.A.	Investigative	[27]
MERCK-544	DMD25I6	Discovery agent	N.A.	Investigative	[30]
N-benzyl-N-(phenylsulfonyl)benzamide	DMT2GSI	Discovery agent	N.A.	Investigative	[17]
PF-877423	DM49MYE	Discovery agent	N.A.	Investigative	[31]
Piperidine-1-carboxylic acid adamantan-2-yl ester	DMF375O	Discovery agent	N.A.	Investigative	[32]
Piperidine-1-carboxylic acid adamantan-2-ylamide	DMHZFK1	Discovery agent	N.A.	Investigative	[32]
SKI-2852	DMJL6HX	Metabolic syndrome x	5C50-5D2Z	Investigative	[26]
Tormentic acid methyl ester	DMDG0HK	Discovery agent	N.A.	Investigative	[6]
[(125)I] RB129	DMX0G7E	Discovery agent	N.A.	Investigative	[33]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Type 2 diabetes	5A11	Liver tissue	2.03E-01	-0.01	-0.08
Coronary artery disease	BA80-BA8Z	Peripheral blood	3.53E-01	0.11	0.56
Familial hypercholesterolemia	5A11	Whole blood	1.35E-01	-0.16	-0.79

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Corticosteroid 11-beta-dehydrogenase 1 (HSD11B1) DME Info
• Gene Name: HSD11B1

2 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cortisone Acetate	DMG8K57	Acne vulgaris	ED80	Approved	[34]
Nabumetone	DMAT2XH	Osteoarthritis	FA00-FA05	Approved	[35]

1 Investigative Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dehydrocorticosterone	DM48KMB	N. A.	N. A.	Investigative	[34]

References

• [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.
• [2] 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.
• [3] Incyte's Selective Oral Inhibitor Of 11beta-HSD1 Demonstrates Improvements In Insulin Sensitivity And Lowers Cholesterol Levels In Type 2 Diabetics. Incyte. 2008.
• [4] New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches. 2012. Chapter 5. Page(131).
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] 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.
• [7] Selection and early clinical evaluation of the brain-penetrant 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor UE2343 (Xanamem?). Br J Pharmacol. 2017 Mar;174(5):396-408.
• [8] Clinical pipeline report, company report or official report of AstraZeneca (2011).
• [9] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027626)
• [10] Repurposing Diabetes Drugs for Brain Insulin Resistance in Alzheimer Disease. before print June 15, 2014.
• [11] 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.
• [12] 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.
• [13] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027759)
• [14] Current and future drug targets in weight management. Pharm Res. 2011 Aug;28(8):1792-818.
• [15] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [16] The discovery of azepane sulfonamides as potent 11beta-HSD1 inhibitors. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4563-5.
• [17] 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.
• [18] 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.
• [19] Discovery of orally active butyrolactam 11beta-HSD1 inhibitors. Bioorg Med Chem Lett. 2006 Nov 1;16(21):5555-60.
• [20] 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.
• [21] Discovery and biological evaluation of adamantyl amide 11beta-HSD1 inhibitors. Bioorg Med Chem Lett. 2007 May 15;17(10):2838-43.
• [22] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [23] The discovery of 2-anilinothiazolones as 11beta-HSD1 inhibitors. Bioorg Med Chem Lett. 2007 Nov 15;17(22):6056-61.
• [24] Oxazolones as potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1. Bioorg Med Chem Lett. 2007 Sep 1;17(17):4837-40.
• [25] 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.
• [26] 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. (Target id: 2763).
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Azabicyclic sulfonamides as potent 11beta-HSD1 inhibitors. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1551-4.
• [31] The development and SAR of pyrrolidine carboxamide 11beta-HSD1 inhibitors. Bioorg Med Chem Lett. 2010 May 1;20(9):2897-902.
• [32] Discovery and optimization of adamantyl carbamate inhibitors of 11-HSD1. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6725-9.
• [33] 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.
• [34] Comparative enzymology of 11beta-hydroxysteroid dehydrogenase type 1 from six species. J Mol Endocrinol. 2005 Aug;35(1):89-101.
• [35] Reductive metabolism of nabumetone by human liver microsomal and cytosolic fractions: exploratory prediction using inhibitors and substrates as marker probes. Eur J Drug Metab Pharmacokinet. 2015 Jun;40(2):127-35.