Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality

被引：32

作者：

Butler, Christopher R. ^{[1
]}

Ogilvie, Kevin ^{[3
]}

Martinez-Alsina, Luis ^{[3
]}

Barreiro, Gabriela ^{[1
]}

Beck, Elizabeth M. ^{[1
]}

Nolan, Charles E. ^{[2
]}

Atchison, Kevin ^{[2
]}

Benvenuti, Eric ^{[5
]}

Buzon, Leanne ^{[3
]}

Doran, Shawn ^{[5
]}

Gonzales, Cathleen ^{[2
]}

Helal, Christopher J. ^{[3
]}

Hou, Xinjun ^{[1
]}

Hsu, Mei-Hui ^{[6
]}

Johnson, Eric F. ^{[6
]}

Lapham, Kimberly ^{[5
]}

Lanyon, Lorraine ^{[5
]}

Parris, Kevin ^{[4
]}

O'Neil, Brian T. ^{[3
]}

Riddell, David ^{[2
]}

Robshaw, Ashley ^{[2
]}

Vajdos, Felix ^{[4
]}

Brodney, Michael A. ^{[1
]}

机构：

[1] Pfizer Worldwide Res & Dev, Neurosci & Pain Med Chem, 610 Main St, Cambridge, MA 02139 USA

[2] Pfizer Worldwide Res & Dev, Neurosci & Pain Res Unit, 610 Main St, Cambridge, MA 02139 USA

[3] Pfizer Worldwide Res & Dev, Neurosci & Pain Med Chem, 445 Eastern Point Rd, Groton, CT 06340 USA

[4] Pfizer Worldwide Res & Dev, Ctr Chem Innovat & Excellence, 445 Eastern Point Rd, Groton, CT 06340 USA

[5] Pfizer Worldwide Res & Dev, Pharmacokinet Dynam & Metab, 445 Eastern Point Rd, Groton, CT 06340 USA

[6] Scripps Res Inst, Mol & Expt Med, 10550 Torrey Pines Rd, La Jolla, CA 92024 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 01期

基金：

美国能源部; 美国国家卫生研究院;

关键词：

ALZHEIMERS-DISEASE; MOLECULAR-GENETICS; AMYLOID-BETA; A-BETA; BRAIN; CYP2D6; SYSTEM; SERIES; HYPOTHESIS; REDUCTION;

D O I：

10.1021/acs.jmedchem.6b01451

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A growing subset of beta-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability, and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor.

引用

页码：386 / 402

页数：17

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