Details

Autor(en) / Beteiligte

• Ye, Xiang-Yang
• Chen, Stephanie Y
• Wu, Shung
• Yoon, David S
• Wang, Haixia
• Hong, Zhenqiu
• O’Connor, Stephen P
• Li, Jun
• Li, James J
• Kennedy, Lawrence J
• Walker, Steven J
• Nayeem, Akbar
• Sheriff, Steven
• Camac, Daniel M
• Ramamurthy, Vidyhashankar
• Morin, Paul E
• Zebo, Rachel
• Taylor, Joseph R
• Morgan, Nathan N
• Ponticiello, Randolph P
• Harrity, Thomas
• Apedo, Atsu
• Golla, Rajasree
• Seethala, Ramakrishna
• Wang, Mengmeng
• Harper, Timothy W
• Sleczka, Bogdan G
• He, Bin
• Kirby, Mark
• Leahy, David K
• Li, Jianqing
• Hanson, Ronald L
• Guo, Zhiwei
• Li, Yi-Xin
• DiMarco, John D
• Scaringe, Raymond
• Maxwell, Brad
• Moulin, Frederick
• Barrish, Joel C
• Gordon, David A
• Robl, Jeffrey A

Titel

Discovery of Clinical Candidate 2‑((2S,6S)‑2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3′-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor

Ist Teil von

• Journal of medicinal chemistry, 2017-06, Vol.60 (12), p.4932-4948

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11β-hydroxysteroid dehydrogenase type 2 (11β-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 11β-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.