2. Academic Validation
  3. Discovery of an Extremely Potent Thiazine-Based β-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose

Discovery of an Extremely Potent Thiazine-Based β-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose

  • J Med Chem. 2019 Oct 24;62(20):9331-9337. doi: 10.1021/acs.jmedchem.9b01140.
Genta Tadano,  Kazuo Komano,  Shuhei Yoshida,  Shinji Suzuki,  Kenji Nakahara,  Kouki Fuchino,  Kazuki Fujimoto,  Eriko Matsuoka,  Takahiko Yamamoto,  Naoya Asada,  Hisanori Ito,  Gaku Sakaguchi,  Naoki Kanegawa,  Yasuto Kido,  Shigeru Ando,  Tamio Fukushima,  Ard Teisman,  Vijay Urmaliya,  Deborah Dhuyvetter,  Herman Borghys,  An Van Den Bergh,  Nigel Austin,  Harrie J M Gijsen,  Yoshinori Yamano,  Yasuyoshi Iso,  Ken-Ichi Kusakabe
PMID: 31549838 DOI: 10.1021/acs.jmedchem.9b01140
Abstract

Genetic evidence points to deposition of Amyloid-β (Aβ) as a causal factor for Alzheimer's disease. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead 1, we describe the discovery of a thiazine-based BACE1 Inhibitor 5 with robust Aβ reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5 achieved sustained Aβ reduction of 80% at trough level.

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