Discovery of Potent and Centrally Active 6-Substituted 5-Fluoro-1,3-dihydro-oxazine β-Secretase (BACE1) Inhibitors via Active Conformation Stabilization
| Autor: | Takahiko Yamamoto, Yasuyoshi Iso, Harrie J.M. Gijsen, Tsuyoshi Hasegawa, Tamio Fukushima, Hisanori Ito, Yoshinori Yamano, Ken-ichi Kusakabe, Yasuto Kido, Herman Borghys, Motoko Hosono, Kenji Nakahara, Kouki Fuchino, Yusuke Sako, Shigeru Ando, Naoya Asada, Kazuo Komano, Gaku Sakaguchi, Masayoshi Ogawa, Genta Tadano, Chie Unemura, Deborah Dhuyvetter, Shuichi Ohnishi |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pyrazine Protein Conformation Stereochemistry hERG 01 natural sciences Rats Sprague-Dawley Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Protein structure In vivo Oxazines Drug Discovery Animals Humans Structure–activity relationship Potency Tissue Distribution Enzyme Inhibitors Dose-Response Relationship Drug biology 010405 organic chemistry Drug discovery Brain Rats 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology chemistry biology.protein Molecular Medicine Efflux Amyloid Precursor Protein Secretases |
| Zdroj: | Journal of Medicinal Chemistry. 61:5525-5546 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b00011 |
| Popis: | β-Secretase (BACE1) has an essential role in the production of amyloid β peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux. The close analogue of 5-fluoro-oxazine 8 reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition. Changing to a pyrazine followed by optimization of substituents on both the oxazine and the pyrazine culminated in 24 with robust Aβ reduction in vivo at low doses as well as reduced CYP2D6 inhibition. On the basis of the X-ray analysis and the QM calculation of given dihydro-oxazines, we reasoned that the substituents at the 6-position as well as the 5-fluorine on the oxazine would stabilize a bioactive conformation to increase potency. |
| Databáze: | OpenAIRE |
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