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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