2. Academic Validation
  3. Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies

Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies

  • J Med Chem. 2019 Nov 27;62(22):10062-10097. doi: 10.1021/acs.jmedchem.9b01090.
Harold G Selnick 1,  J Fred Hess 1,  Cuyue Tang 1,  Kun Liu 1,  Joel B Schachter 1,  Jeanine E Ballard 1,  Jacob Marcus 1,  Daniel J Klein 1,  Xiaohai Wang 1,  Michelle Pearson 1,  Mary J Savage 1,  Ramesh Kaul 2,  Tong-Shuang Li 2,  David J Vocadlo 2,  Yuanxi Zhou 2,  Yongbao Zhu 2,  Changwei Mu 3,  Yaode Wang 3,  Zhongyong Wei 3,  Chang Bai 3,  Joseph L Duffy 1,  Ernest J McEachern 2
Affiliations

Affiliations

  • 1 Merck & Co., Inc. , 2015 Galloping Hill Road , Kenilworth , New Jersey 07033 , United States.
  • 2 Alectos Therapeutics Inc. , 8999 Nelson Way , Burnaby , British Columbia V5A 4B5 , Canada.
  • 3 Pharmaron Beijing Co. Ltd. , 6 Taihe Road, BDA , Beijing 100176 , P. R. China.
PMID: 31487175 DOI: 10.1021/acs.jmedchem.9b01090
Abstract

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.

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