Design and Synthesis of Potent, Orally Efficacious Hydroxyethylamine Derived β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors

被引：37

作者：

Dineen, Thomas A. ^{[1
]}

Weiss, Matthew M. ^{[1
]}

Williamson, Toni ^{[2
]}

Acton, Paul ^{[2
]}

Babu-Khan, Safura ^{[3
]}

Bartberger, Michael D.

Brown, James ^{[1
]}

Chen, Kui

Cheng, Yuan ^{[1
]}

Citron, Martin ^{[2
]}

Crogan, Michael D. ^{[1
]}

Dunn, Robert T., II

Esmay, Joel

Graceffa, Russell F. ^{[1
]}

Harriedt, Scott S. ^{[1
]}

Hickman, Dean

Hitchcock, Stephen A. ^{[1
]}

Horne, Daniel B. ^{[1
]}

Huang, Hongbing ^{[1
]}

Imbeah-Ampiah, Ronke ^{[1
]}

Judd, Ted ^{[1
]}

Kaller, Matthew R. ^{[1
]}

Kreiman, Charles R. ^{[1
]}

La, Daniel S. ^{[1
]}

Li, Vivian

Lopez, Patricia ^{[1
]}

Louie, Steven

Monenschein, Holger ^{[1
]}

Nguyen, Thomas T. ^{[1
]}

Pennington, Lewis D. ^{[1
]}

Miguel, Tisha Sin ^{[3
]}

Sickmier, E. Allen

Vargas, Hugo M.

Wahl, Robert C. ^{[3
]}

Wen, Paul H.

Whittington, Douglas A.

Wood, Stephen

Xue, Qiufen ^{[1
]}

Yang, Bryant H. ^{[1
]}

Patel, Vinod F.

Zhong, Wenge ^{[1
]}

机构：

[1] Amgen Inc, Chemica Res & Discovery, Cambridge, MA 02142 USA

[2] Amgen Inc, Dept Neurosci, Thousand Oaks, CA 91320 USA

[3] Amgen Inc, Dept HTS & Mol Pharmacol, Thousand Oaks, CA 91320 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 21期

关键词：

ALZHEIMERS-DISEASE; P-GLYCOPROTEIN; CASCADE HYPOTHESIS; PART; SECRETASE; DISCOVERY; 2ND-GENERATION; BRAIN; MICE; IDENTIFICATION;

D O I：

10.1021/jm300118s

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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 zentral amyloid-beta peptide (A beta) levels in wild-type rats following oral dosing. In this article, we describe further modificitions 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 A beta levels in rat CSF and brain following oral dosing, and compound 37 exhibited an improved cardiovascular safety profile relative to 1.

引用

页码：9025 / 9044

页数：20

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