1382799-79-2Relevant academic research and scientific papers
Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies
Selnick, Harold G.,Hess, J. Fred,Tang, Cuyue,Liu, Kun,Schachter, Joel B.,Ballard, Jeanine E.,Marcus, Jacob,Klein, Daniel J.,Wang, Xiaohai,Pearson, Michelle,Savage, Mary J.,Kaul, Ramesh,Li, Tong-Shuang,Vocadlo, David J.,Zhou, Yuanxi,Zhu, Yongbao,Mu, Changwei,Wang, Yaode,Wei, Zhongyong,Bai, Chang,Duffy, Joseph L.,McEachern, Ernest J.
, p. 10062 - 10097 (2019/10/14)
Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clinical trials.
SELECTIVE GLYCOSIDASE INHIBITORS AND USES THEREOF
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, (2012/07/13)
The invention provides compounds with enhanced permeability for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, accumulation or deficiency of O-GlcNAc.
SELECTIVE GLYCOSIDASE INHIBITORS AND USES THEREOF
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, (2012/12/13)
The invention provides compounds for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to deficiency or overexpression of O-Glc NAcase, accumulation or deficiency of O-Glc NAc.
