Evolution of Tertiary Carbinamine BACE-1 Inhibitors: Aβ Reduction in Rhesus CSF upon Oral Dosing

被引:16
作者
Nantermet, Philippe G. [1 ]
Rajapakse, Hemaka A. [1 ]
Stanton, Mathew G. [1 ]
Stauffer, Shaun R. [1 ]
Barrow, James C. [1 ]
Gregro, Allison R. [1 ]
Moore, Keith P. [1 ]
Steinbeiser, Melissa A. [1 ]
Swestock, John [1 ]
Selnick, Harold G. [1 ]
Graham, Samuel L. [1 ]
McGaughey, Georgia B. [2 ]
Colussi, Dennis [3 ]
Lai, Ming-Tain [3 ]
Sankaranarayanan, Sethu [3 ]
Simon, Adam J. [3 ]
Munshi, Sanieev [4 ]
Cook, Jacquelynn J. [5 ]
Holahan, Marie A. [5 ]
Michener, Maria S. [5 ]
Vacca, Joseph P. [1 ]
机构
[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA
[2] Merck Res Labs, Dept Mol Syst, West Point, PA 19486 USA
[3] Merck Res Labs, Dept Alzheimers Res, West Point, PA 19486 USA
[4] Merck Res Labs, Dept Biol Struct, West Point, PA 19486 USA
[5] Merck Res Labs, Dept Imaging, West Point, PA 19486 USA
关键词
alzheimer's disease; a beta reduction; inhibitors; BACE-1; beta-secretase; ALZHEIMERS-DISEASE; P-GLYCOPROTEIN; IN-VITRO; PROTEASE INHIBITORS; SECRETASE BACE-1; HIV-1; PROTEASE; DISCOVERY; STRATEGIES; DRUGS; CNS;
D O I
10.1002/cmdc.200800308
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Incorporation of an isonicotinic core containing a P3 methylcyclopropyl group into our previously reported ox-adiazolyl tertiary carbinamine based BACE-1 inhibitors has led to the identification of the exquisitely potent inhibitor 6, which displays good permeability and low susceptibility to the P-gp efflux pump. Upon co-dosing with CYP 3A4 inhibitor ritonavir, tertiary carbinamine 6 was found to be orally bioavailable. Following twice daily oral administration to monkeys, it was shown to penetrate the CNS and lower Aβ42 levels in the CSF by >40% over the course of a 3 day experiment. Further structural improvements aimed at optimization of pharmacokinetics and brain penetration will be the subject of future work, as will studies of the impact of central BACE-1 inhibitor-mediated Aβ42 lowering on cognition. © 2009 wiley -VCH Verlag GmbH & Co.
引用
收藏
页码:37 / 40
页数:4
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