Trifluoromethyl Dihydrothiazine‐Based β‐Secretase (BACE1) Inhibitors with Robust Central β‐Amyloid Reduction and Minimal Covalent Binding Burden
| Autor: | Yasuyoshi Iso, Shigeru Ando, Harrie J.M. Gijsen, Yasuto Kido, Shinji Suzuki, Herman Borghys, Kenji Morimoto, Vijay Urmaliya, Deborah Dhuyvetter, Takahiko Yamamoto, Ard Teisman, Gaku Sakaguchi, Naoki Kanegawa, Nigel Austin, Eriko Matsuoka, An Van Den Bergh, Hisanori Ito, Takuya Oguma, Francois Paul Bischoff, Tamio Fukushima, Peter Verboven, Tomoyuki Kawachi, Kenji Nakahara, Yoshinori Yamano, Kosuke Anan, Ken-ichi Kusakabe |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Models Molecular hERG Thiazines Pharmacology 01 natural sciences Biochemistry Mice Structure-Activity Relationship chemistry.chemical_compound Dogs Oral administration Oxazines Drug Discovery Hydrolase Amyloid precursor protein Animals Aspartic Acid Endopeptidases Humans General Pharmacology Toxicology and Pharmaceutics Mice Knockout chemistry.chemical_classification Mice Inbred ICR Amyloid beta-Peptides Trifluoromethyl Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Chemistry Organic Chemistry Rats 0104 chemical sciences Mice Inbred C57BL 010404 medicinal & biomolecular chemistry Enzyme Drug Design Hepatocytes Microsomes Liver biology.protein Microsome Molecular Medicine Efflux Amyloid Precursor Protein Secretases |
| Zdroj: | ChemMedChem. 14:1894-1910 |
| ISSN: | 1860-7187 1860-7179 |
| DOI: | 10.1002/cmdc.201900478 |
| Popis: | The β-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as β-secretase) is a promising target for the treatment of Alzheimer's disease. A pKa lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF3 dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide). Optimization of 8 led to the discovery of 15 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide) with an excellent balance of potency, hERG inhibition, P-gp efflux, and metabolic stability. Oral administration of 8 elicited robust Aβ reduction in dog even at 0.16 mg/kg. Reflecting the reduced hERG inhibitory activity, no QTc prolongation was observed at high doses. The potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [14 C]-KCN in human liver microsomes. Utilizing covalent binding (CVB) in human hepatocytes and the maximum projected human dosage, the daily CVB burden of 15 was calculated to be at an acceptable value of below 1 mg/day. However, hepatotoxicity was observed when 15 was subjected to a two-week tolerance study in dog, which prevented further evaluation of this compound. |
| Databáze: | OpenAIRE |
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