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Title: Discovery of Clinical Candidate 2-((2 S,6 S)-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

Abstract

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 (IC 50 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 (ED 50 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.


Citation Formats

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., and Robl, Jeffrey A. Discovery of Clinical Candidate 2-((2S,6 S)-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. United States: N. p., 2017. Web. doi:10.1021/acs.jmedchem.7b00211.
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. Discovery of Clinical Candidate 2-((2S,6 S)-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. United States. doi:10.1021/acs.jmedchem.7b00211.
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., and Robl, Jeffrey A. Mon . "Discovery of Clinical Candidate 2-((2S,6 S)-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". United States. doi:10.1021/acs.jmedchem.7b00211.
@article{osti_1397306,
title = {Discovery of Clinical Candidate 2-((2S,6 S)-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},
author = {Ye, Xiang-Yang and Chen, Stephanie Y. and Wu, Shung and Yoon, David S. and Wang, Haixia and Hong, Zhenqiu and O’Connor, Stephen P. and Li, Jun and Li, James J. and Kennedy, Lawrence J. and Walker, Steven J. and Nayeem, Akbar and Sheriff, Steven and Camac, Daniel M. and Ramamurthy, Vidyhashankar and Morin, Paul E. and Zebo, Rachel and Taylor, Joseph R. and Morgan, Nathan N. and Ponticiello, Randolph P. and Harrity, Thomas and Apedo, Atsu and Golla, Rajasree and Seethala, Ramakrishna and Wang, Mengmeng and Harper, Timothy W. and Sleczka, Bogdan G. and He, Bin and Kirby, Mark and Leahy, David K. and Li, Jianqing and Hanson, Ronald L. and Guo, Zhiwei and Li, Yi-Xin and DiMarco, John D. and Scaringe, Raymond and Maxwell, Brad and Moulin, Frederick and Barrish, Joel C. and Gordon, David A. and Robl, Jeffrey A.},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.7b00211},
journal = {Journal of Medicinal Chemistry},
number = 12,
volume = 60,
place = {United States},
year = {Mon Jun 05 00:00:00 EDT 2017},
month = {Mon Jun 05 00:00:00 EDT 2017}
}