Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3′-hydroxyazetidin-1-yl)ethanone [BMS-8163361, an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor

被引：10

作者：

Ye, Xiang-Yang ^{[1
]}

Chen, Stephanie Y. ^{[1
]}

Wu, Shung ^{[1
]}

Yoon, David S. ^{[1
]}

Wang, Haixia ^{[1
]}

Hong, Zhenqiu ^{[1
]}

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

Li, Jun ^{[1
]}

Li, James J. ^{[1
]}

Kennedy, Lawrence J. ^{[1
]}

Walker, Steven J. ^{[1
,9
]}

Nayeem, Akbar ^{[3
,9
]}

Sheriff, Steven ^{[3
]}

Camac, Daniel M. ^{[3
]}

Ramamurthy, Vidyhashankar ^{[3
,9
]}

Morin, Paul E. ^{[10
]}

Zebo, Rachel ^{[4
]}

Taylor, Joseph R. ^{[4
]}

Morgan, Nathan N. ^{[4
]}

Ponticiello, Randolph P. ^{[4
]}

Harrity, Thomas ^{[4
]}

Apedo, Atsu ^{[2
]}

Golla, Rajasree ^{[5
]}

Seethala, Ramakrishna

Wang, Mengmeng ^{[2
]}

Harper, Timothy W. ^{[2
]}

Sleczka, Bogdan G. ^{[2
]}

He, Bin ^{[4
]}

Kirby, Mark ^{[4
]}

Leahy, David K. ^{[6
]}

Li, Jianqing

Hanson, Ronald L. ^{[6
]}

Guo, Zhiwei ^{[6
]}

Li, Yi-Xin ^{[2
]}

DiMarco, John D. ^{[11
]}

Scaringe, Raymond ^{[11
]}

Maxwell, Brad ^{[7
]}

Moulin, Frederick ^{[8
]}

Barrish, Joel C. ^{[1
]}

Gordon, David A. ^{[4
]}

Robl, Jeffrey A. ^{[1
]}

机构：

[1] Bristol Myers Squibb, Discovery Chem, 350 Carter Rd, Princeton, NJ 08540 USA

[2] Bristol Myers Squibb, Pharmaceut Candidate Optimizat, 350 Carter Rd, Princeton, NJ 08540 USA

[3] Bristol Myers Squibb, Comp Assisted Drug Design, 350 Carter Rd, Princeton, NJ 08540 USA

[4] Bristol Myers Squibb, Metab Dis Biol, 350 Carter Rd, Princeton, NJ 08540 USA

[5] Bristol Myers Squibb, Lead Evaluat, 350 Carter Rd, Princeton, NJ 08540 USA

[6] Bristol Myers Squibb, Proc Chem, 350 Carter Rd, Princeton, NJ 08540 USA

[7] Bristol Myers Squibb, Chem Synth, 350 Carter Rd, Princeton, NJ 08540 USA

[8] Bristol Myers Squibb, Discovery Toxicol, Res & Dev, 350 Carter Rd, Princeton, NJ 08540 USA

[9] Bristol Myers Squibb, Mol Struct & Design, POB 4000, Princeton, NJ 08543 USA

[10] Bristol Myers Squibb, Prot Sci, POB 4000, Princeton, NJ 08543 USA

[11] Bristol Myers Squibb, Solid State Chem, Res & Dev, POB 4000, Princeton, NJ 08543 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 12期

关键词：

METABOLIC SYNDROME; 11-BETA-HSD1; INHIBITORS; THERAPEUTIC TARGET; ACCURATE DOCKING; HIGHLY POTENT; MICE; DISEASE; DESIGN; GLIDE; CORTISOL;

D O I：

10.1021/acs.jmedchem.7b00211

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11 beta-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic pituitary adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.

引用

页码：4932 / 4948

页数：17

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