Rational design and synthesis of selective BACE-1 inhibitors

被引：52

作者：

Brady, SF

Singh, S

Crouthamel, MC

Holloway, MK

Coburn, CA

Garsky, VM

Bogusky, M

Pennington, MW

Vacca, JP

Hazuda, D

Lai, MT ^{[1
]}

机构：

[1] Merck Res Labs, Dept Biol Chem, W Point, PA 19486 USA

[2] Merck Res Labs, Dept Med Chem, W Point, PA 19486 USA

[3] Bachem Biosci Inc, King Of Prussia, PA 19406 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 03期

关键词：

D O I：

10.1016/j.bmcl.2003.11.061

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

An effective approach for enhancing the selectivity of beta-site amyloid precursor protein cleaving enzyme (BACE 1) inhibitors is developed based on the unique features of the S1' pocket of the enzyme. A series of low molecular weight ( < 600) compounds were synthesized with different moieties at the P1' position. The selectivity of BACE 1 inhibitors versus cathepsin D and renin was enhanced 120-fold by replacing the hydrophobic propyl group with a hydrophilic propionic acid group. (C) 2003 Elsevier Ltd. All rights reserved.

引用

收藏

页码：601 / 604

页数：4

相关论文

共 29 条

[1] CRYSTAL-STRUCTURES OF NATIVE AND INHIBITED FORMS OF HUMAN CATHEPSIN-D - IMPLICATIONS FOR LYSOSOMAL TARGETING AND DRUG DESIGN [J].

BALDWIN, ET ;

BHAT, TN ;

GULNIK, S ;

HOSUR, MV ;

SOWDER, RC ;

CACHAU, RE ;

COLLINS, J ;

SILVA, AM ;

ERICKSON, JW .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (14) :6796-6800

[2]

BODANSZKY A, 1994, PRACTICE PEPTIDE SYN, P38

[3] A splice variant of β-secretase deficient in the amyloidogenic processing of the amyloid precursor protein [J].

Bodendorf, U ;

Fischer, F ;

Bodian, D ;

Multhaup, G ;

Paganetti, P .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (15) :12019-12023

[4] Synthesis of a tripeptide derivative containing the Phe-Arg hydroxyethylene dipeptide isostere [J].

Brewer, M ;

Rich, DH .

ORGANIC LETTERS, 2001, 3 (06) :945-948

[5] HYDROBORATION .36. DIRECT ROUTE TO 9-BORABICYCLO[3.3.1]NONANE VIA CYCLIC HYDROBORATION OF 1,5-CYCLOOCTADIENE - 9-BORABICYCLO[3.3.1]NONANE AS A UNIQUELY SELECTIVE REAGENT FOR HYDROBORATION OF OLEFINS [J].

BROWN, HC ;

KNIGHTS, EF ;

SCOUTEN, CG .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1974, 96 (25) :7765-7770

[6]

BROWN HC, 1980, SYNTHESIS-STUTTGART, P151

[7] BACE1 is the major β-secretase for generation of Aβ peptides by neurons [J].

Cai, HB ;

Wang, YS ;

McCarthy, D ;

Wen, HJ ;

Borchelt, DR ;

Price, DL ;

Wong, PC .

NATURE NEUROSCIENCE, 2001, 4 (03) :233-234

[8] A GREATLY IMPROVED PROCEDURE FOR RUTHENIUM TETRAOXIDE CATALYZED OXIDATIONS OF ORGANIC-COMPOUNDS [J].

CARLSEN, PHJ ;

KATSUKI, T ;

MARTIN, VS ;

SHARPLESS, KB .

JOURNAL OF ORGANIC CHEMISTRY, 1981, 46 (19) :3936-3938

[9] β-secretase as a target for the treatment of Alzheimer's disease [J].

Citron, M .

JOURNAL OF NEUROSCIENCE RESEARCH, 2002, 70 (03) :373-379

[10] Proteolytic activation of recombinant pro-memapsin 2 (pro-β-secretase) studied with new fluorogenic substrates [J].

Ermolieff, J ;

Loy, JA ;

Koelsch, G ;

Tang, J .

BIOCHEMISTRY, 2000, 39 (40) :12450-12456