Synthesis and γ-secretase activity of APP substrate-based hydroxyethylene dipeptide isosteres

被引：29

作者：

Nadin, A

Owens, AP

Castro, JL

Harrison, T

Shearman, MS

机构：

[1] Neurosci Res Ctr, Merck Sharp & Dohme Res Labs, Dept Med Chem, Harlow CM20 2QR, Essex, England

[2] Neurosci Res Ctr, Merck Sharp & Dohme Res Labs, Dept Biol Mol, Harlow CM20 2QR, Essex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2003年 / 13卷 / 01期

关键词：

D O I：

10.1016/S0960-894X(02)00840-5

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Two new APP substrate-based hydroxyethylene isosteres (AT and VI) were prepared and their dipeptide conjugates shown not to inhibit the gamma-secretase-mediated formation of either Abeta1-40 or Abeta1-42. The FG isostere and a des-hydroxy hydroxyethylene isostere also gave inactive compounds. Conversely, a number of compounds containing the intact substrate-unrelated Phe-Phe (FF) hydroxyethylene isostere were shown to be potent inhibitors (ED50 = 14-732 nM). These results show that the factors governing the substrate-based design of gamma-secretase inhibitors are more complicated than first thought. (C) 2002 Elsevier Science Ltd. All rights reserved.

引用

收藏

页码：37 / 41

页数：5

相关论文

共 27 条

[1] Pharmacological knock-down of the presenilin 1 heterodimer by a novel γ-secretase inhibitor -: Implications for presenilin biology [J].

Beher, D ;

Wrigley, JDJ ;

Nadin, A ;

Evin, G ;

Masters, CL ;

Harrison, T ;

Castro, JL ;

Shearman, MS .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (48) :45394-45402

[2]

BRISTOLMYERS SQUIBB, 1997, Patent No. 5703129

[3] Activity-dependent isolation of the presenilin-γ-secretase complex reveals nicastrin and a γ substrate [J].

Esler, WP ;

Kimberly, WT ;

Ostaszewski, BL ;

Ye, WJ ;

Diehl, TS ;

Selkoe, DJ ;

Wolfe, MS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (05) :2720-2725

[4] Biomedicine - A portrait of Alzheimer secretases - New features and familiar faces [J].

Esler, WP ;

Wolfe, MS .

SCIENCE, 2001, 293 (5534) :1449-1454

[5] Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1 [J].

Esler, WP ;

Kimberly, WT ;

Ostaszewski, BL ;

Diehl, TS ;

Moore, CL ;

Tsai, JY ;

Rahmati, T ;

Xia, WM ;

Selkoe, DJ ;

Wolfe, MS .

NATURE CELL BIOLOGY, 2000, 2 (07) :428-434

[6] Distinct intramembrane cleavage of the β-amyloid precursor protein family resembling γ-secretase-like cleavage of Notch [J].

Gu, YJ ;

Misonou, H ;

Sato, T ;

Dohmae, N ;

Takio, K ;

Ihara, Y .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (38) :35235-35238

[7] A combinatorial approach to the identification of dipeptide aldehyde inhibitors of β-amyloid production [J].

Higaki, JN ;

Chakravarty, S ;

Bryant, CM ;

Cowart, LR ;

Harden, P ;

Scardina, JM ;

Mavunkel, B ;

Luedtke, GR ;

Cordell, B .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (19) :3889-3898

[8] ESTER HOMOLOGATION REVISITED - A RELIABLE, HIGHER YIELDING AND BETTER UNDERSTOOD PROCEDURE [J].

KOWALSKI, CJ ;

REDDY, RE .

JOURNAL OF ORGANIC CHEMISTRY, 1992, 57 (26) :7194-7208

[9] Presenilin-dependent γ-secretase-like intramembrane cleavage of ErbB4 [J].

Lee, HJ ;

Jung, KM ;

Huang, YZ ;

Bennett, LB ;

Lee, JS ;

Mei, L ;

Kim, TW .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (08) :6318-6323

[10] Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1 [J].

Li, YM ;

Xu, M ;

Lai, MT ;

Huang, Q ;

Castro, JL ;

DiMuzio-Mower, J ;

Harrison, T ;

Lellis, C ;

Nadin, JL ;

Neduvelil, JG ;

Register, RB ;

Sardana, MK ;

Shearman, MS ;

Smith, AL ;

Shi, XP ;

Yin, KC ;

Shafer, JA ;

Gardell, SJ .

NATURE, 2000, 405 (6787) :689-694