Design and synthesis of potent, orally efficacious hydroxyethylamine derived β-Site amyloid precursor protein cleaving enzyme (Bace1) inhibitors

Dineen T.A.; Weiss M.M.; Williamson T.; Acton P.; Babu-Khan S.; Bartberger M.D.; Brown J.; Chen K.; Cheng Y.; Citron M.; Croghan M.D.; Dunn R.T.; Esmay J.; Graceffa R.F.; Harried S.S.; Hickman D.; Hitchcock S.A.; Horne D.B.; Huang H.; Imbeah-Ampiah R.; Judd T.; Kaller M.R.; Kreiman C.R.; La D.S.; Li V.

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Design and synthesis of potent, orally efficacious hydroxyethylamine derived β-Site amyloid precursor protein cleaving enzyme (Bace1) inhibitors

机译：设计和合成有效的，口服有效的羟乙基胺衍生的β-Site淀粉样前体蛋白裂解酶（Bace1）抑制剂

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We have previously shown that hydroxyethylamines can be potent inhibitors of the BACE1 enzyme and that the generation of BACE1 inhibitors with CYP 3A4 inhibitory activities in this scaffold affords compounds (e.g., 1) with sufficient bioavailability and pharmacokinetic profiles to reduce central amyloid-β peptide (Aβ) levels in wild-type rats following oral dosing. In this article, we describe further modifications of the P1-phenyl ring of the hydroxyethylamine series to afford potent, dual BACE1/CYP 3A4 inhibitors which demonstrate improved penetration into the CNS. Several of these compounds caused robust reduction of Aβ levels in rat CSF and brain following oral dosing, and compound 37 exhibited an improved cardiovascular safety profile relative to 1.

机译：先前我们已经证明羟乙胺可能是BACE1酶的有效抑制剂，并且在该支架中具有CYP 3A4抑制活性的BACE1抑制剂的产生提供了具有足够生物利用度和药代动力学特征的化合物（例如1），以减少中央淀粉样β肽（口服后野生型大鼠的Aβ）水平。在本文中，我们描述了羟乙胺系列的P1-苯环的进一步修饰，以提供有效的双BACE1 / CYP 3A4抑制剂，该抑制剂表现出对CNS的改善渗透性。这些化合物中的几种引起口服给药后大鼠CSF和大脑中Aβ含量的强烈降低，并且化合物37的心血管安全性相对于1。

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《Journal of Medicinal Chemistry》 |2012年第21期|共20页
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Dineen T.A.; Weiss M.M.; Williamson T.; Acton P.; Babu-Khan S.; Bartberger M.D.; Brown J.; Chen K.; Cheng Y.; Citron M.; Croghan M.D.; Dunn R.T.; Esmay J.; Graceffa R.F.; Harried S.S.; Hickman D.; Hitchcock S.A.; Horne D.B.; Huang H.; Imbeah-Ampiah R.; Judd T.; Kaller M.R.; Kreiman C.R.; La D.S.; Li V.;
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1. Design and synthesis of potent, orally efficacious hydroxyethylamine derived β-Site amyloid precursor protein cleaving enzyme (Bace1) inhibitors [J] . Dineen T.A., Weiss M.M., Williamson T., Journal of Medicinal Chemistry . 2012,第21期

机译：设计和合成有效的，口服有效的羟乙基胺衍生的β-Site淀粉样前体蛋白裂解酶（Bace1）抑制剂
2. Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation [J] . ONeill Brian T., Beck Elizabeth M., Butler Christopher R., Journal of Medicinal Chemistry . 2018,第10期

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3. Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: Structure based design and in vivo reduction of amyloid β-peptides [J] . RueegerH., LueoendR., MachauerR., Bioorganic and Medicinal Chemistry Letters . 2013,第19期

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4. Pharmacophore Based Virtual Screening, Molecular Docking and Density Functional Theory Approaches to Discover the Potent Beta-Amyloid Precursor Protein (B-App) Inhibitor [C] . G. Shakila, C. Meganathan, N. Sundaraganesan, National Conference on Hierarchically Structured Materials . 2019

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5. beta-Endorphin inhibits the expression of amyloid precursor protein in SK-N-SH neuroblastoma cells expressing high levels of mutant amyloid precursor protein. [D] . Boggeti, Renuka. 2012

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Design and synthesis of potent, orally efficacious hydroxyethylamine derived β-Site amyloid precursor protein cleaving enzyme (Bace1) inhibitors

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