Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1)

被引：5

作者：

Li, Jun ^{[1
]}

Kennedy, Lawrence J. ^{[1
]}

Walker, Steven J. ^{[1
]}

Wang, Haixia ^{[1
]}

Li, James J. ^{[1
]}

Hong, Zhenqiu ^{[1
]}

O'Connor, Stephen P. ^{[1
]}

Ye, Xiang-yang ^{[1
]}

Chen, Stephanie ^{[1
]}

Wu, Shung ^{[1
]}

Yoon, David S. ^{[1
]}

Nayeem, Akbar ^{[2
]}

Camac, Daniel M. ^{[2
]}

Ramamurthy, Vidhyashankar ^{[2
]}

Morin, Paul E. ^{[2
]}

Sheriff, Steven ^{[2
]}

Wang, Mengmeng ^{[1
]}

Harper, Timothy W. ^{[1
]}

Golla, Rajasree ^{[1
]}

Seethala, Ramakrishna ^{[1
]}

Harrity, Thomas ^{[1
]}

Ponticiello, Randolph P. ^{[1
]}

Morgan, Nathan N. ^{[1
]}

Taylor, Joseph R. ^{[1
]}

Zebo, Rachel ^{[1
]}

Maxwell, Brad ^{[2
]}

Moulin, Frederick ^{[1
]}

Gordon, David A. ^{[1
]}

Robl, Jeffrey A. ^{[1
]}

机构：

[1] Bristol Myers Squibb, Res & Dev, POB 5400, Princeton, NJ 08543 USA

[2] Bristol Myers Squibb, Res & Dev, POB 4000, Princeton, NJ 08543 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2018年 / 9卷 / 12期

关键词：

Enzyme inhibitors; human 11 beta-hydroxysteroid dehydrogenase-type 1; 11; beta-HSD-1; trizolopyridine; 1,2,4-triazolopyridinyl-methanol; BMS-823778; high adipose selectivity; type; 2; diabetes; cortisol; cortisone;

D O I：

10.1021/acsmedchemlett.8b00307

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD-1) enzyme (IC50 = 2.3 nM) with >10,000-fold selectivity over 11 beta-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED50 = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.

引用

页码：1170 / 1174

页数：9

共 18 条

[1] The role of mediastinal adipose tissue 11β-hydroxysteroid d ehydrogenase type 1 and glucocorticoid expression in the development of coronary atherosclerosis in obese patients with ischemic heart disease [J].

Atalar, Fatmahan ;

Gormez, Selcuk ;

Caynak, Baris ;

Akan, Gokce ;

Tanriverdi, Gamze ;

Bilgic-Gazioglu, Sema ;

Gunay, Demet ;

Duran, Cihan ;

Akpinar, Belhhan ;

Ozbek, Ugur ;

Buyukdevrim, Ahmet Sevim ;

Yazici, Zeliha .

CARDIOVASCULAR DIABETOLOGY, 2012, 11

[2] 11β-hydroxysteroid dehydrogenase type 1 inhibitors: a review of recent patents [J].

Boyle, Craig D. ;

Kowalski, Timothy J. .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2009, 19 (06) :801-825

[3] Features and development of Coot [J].

Emsley, P. ;

Lohkamp, B. ;

Scott, W. G. ;

Cowtan, K. .

ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 2010, 66 :486-501

[4]

Garcia R A., 2013, PLOS ONE, V8, P1

[5] 11β-Hydroxysteroid Dehydrogenase 1: Translational and Therapeutic Aspects [J].

Gathercole, Laura L. ;

Lavery, Gareth G. ;

Morgan, Stuart A. ;

Cooper, Mark S. ;

Sinclair, Alexandra J. ;

Tomlinson, Jeremy W. ;

Stewart, Paul M. .

ENDOCRINE REVIEWS, 2013, 34 (04) :525-555

[6] Clinical Pharmacokinetics and the Impact of Genetic Polymorphism on a CYP2C19 Substrate, BMS-823778, in Healthy Subjects [J].

Gong, Jiachang ;

Hansen, Lars ;

Iacono, Lisa .

DRUG METABOLISM AND DISPOSITION, 2018, 46 (03) :316-325

[7]

Li Jun, 2014, ACS Med Chem Lett, V5, P803, DOI 10.1021/ml500144h

[8] Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition [J].

Mohler, Eric G. ;

Browman, Kaitlin E. ;

Roderwald, Victoria A. ;

Cronin, Elizabeth A. ;

Markosyan, Stella ;

Bitner, R. Scott ;

Strakhova, Marina I. ;

Drescher, Karla U. ;

Hornberger, Wilfried ;

Rohde, Jeffrey J. ;

Brune, Michael E. ;

Jacobson, Peer B. ;

Rueter, Lynne E. .

JOURNAL OF NEUROSCIENCE, 2011, 31 (14) :5406-5413

[9] 11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess [J].

Morgan, Stuart A. ;

McCabe, Emma L. ;

Gathercole, Laura L. ;

Hassan-Smith, Zaki K. ;

Larner, Dean P. ;

Bujalska, Iwona J. ;

Stewart, Paul M. ;

Tomlinson, Jeremy W. ;

Lavery, Gareth G. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (24) :E2482-E2491

[10] Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease [J].

Morton, Nicholas Michael .

MOLECULAR AND CELLULAR ENDOCRINOLOGY, 2010, 316 (02) :154-164

← 1 2 →