Design and synthesis of highly active Alzheimer's β-secretase (BACE1) inhibitors, KMI-420 and KMI-429, with enhanced chemical stability

被引：94

作者：

Kimura, T

Shuto, D

Hamada, Y

Igawa, N

Kasai, S

Liu, P

Hidaka, K

Hamada, T

Hayashi, Y

Kiso, Y ^{[1
]}

机构：

[1] Kyoto Pharmaceut Univ, Ctr Frontier Res Med Sci, Dept Med Chem, Yamashima Ku, Kyoto 6078412, Japan

[2] Kyoto Pharmaceut Univ, Century COE Program 21st, Yamashima Ku, Kyoto 6078412, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 01期

关键词：

Alzheimer's disease; BACE1; inhibitor; beta-secretase; bioisostere;

D O I：

10.1016/j.bmcl.2004.09.090

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Recently, we reported potent and small-sized BACE1 inhibitors KMI-358 and KMI-370 in which the Glu residue is replaced by a beta-N-oxalyl-DAP (L-alpha,beta-diaminopropionyl) residue at the P-4 position. The beta-N-oxalyl-DAP group is important for enhancing BACE1 inhibitory activity, but these inhibitors isomerized to alpha-N-oxalyl-DAP derivatives in solvents. Hence, we used a tetrazole moiety as a bioisostere of the free carboxylic acid of the oxalyl group. KMI-420 and KMI-429, containing a tetrazole ring, showed improved stability and potent enzyme inhibitory activity. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：211 / 215

页数：5

共 30 条

[21] KMI-008, a novel β-secretase inhibitor containing a hydroxymethylcarbonyl isostere as a transition-state mimic:: Design and synthesis of substrate-based octapeptides [J].

Shuto, D ;

Kasai, S ;

Kimura, T ;

Liu, P ;

Hidaka, K ;

Hamada, T ;

Shibakawa, S ;

Hayashi, Y ;

Hattori, C ;

Szabo, B ;

Ishiura, S ;

Kiso, Y .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (24) :4273-4276

[22] Purification and cloning of amyloid precursor protein β-secretase from human brain [J].

Sinha, S ;

Anderson, JP ;

Barbour, R ;

Basi, GS ;

Caccavello, R ;

Davis, D ;

Doan, M ;

Dovey, HF ;

Frigon, N ;

Hong, J ;

Jacobson-Croak, K ;

Jewett, N ;

Keim, P ;

Knops, J ;

Lieberburg, I ;

Power, M ;

Tan, H ;

Tatsuno, G ;

Tung, J ;

Schenk, D ;

Seubert, P ;

Suomensaari, SM ;

Wang, SW ;

Walker, D ;

Zhao, J ;

McConlogue, L ;

John, V .

NATURE, 1999, 402 (6761) :537-540

[23] Cellular mechanisms of β-amyloid production and secretion [J].

Sinha, S ;

Lieberburg, I .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (20) :11049-11053

[24] AMYLOIDOSIS [J].

SIPE, JD .

ANNUAL REVIEW OF BIOCHEMISTRY, 1992, 61 :947-975

[25] LATHYRISM - EVIDENCE FOR ROLE OF THE NEUROEXCITATORY AMINO-ACID BOAA [J].

SPENCER, PS ;

LUDOLPH, A ;

DWIVEDI, MP ;

ROY, DN ;

HUGON, J ;

SCHAUMBURG, HH .

LANCET, 1986, 2 (8515) :1066-1067

[26] Genes and mechanisms involved in β-amyloid generation and Alzheimer's disease [J].

Steiner, H ;

Capell, A ;

Leimer, U ;

Haass, C .

EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE, 1999, 249 (06) :266-270

[27] Synthesis of potent β-secretase inhibitors containing a hydroxyethylamine dipeptide isostere and their structure-activity relationship studies [J].

Tamamura, H ;

Kato, T ;

Otaka, A ;

Fujii, N .

ORGANIC & BIOMOLECULAR CHEMISTRY, 2003, 1 (14) :2468-2473

[28] Design of substrate-based inhibitors of human β-secretase [J].

Tung, JS ;

Davis, DL ;

Anderson, JP ;

Walker, DE ;

Mamo, S ;

Jewett, N ;

Hom, RK ;

Sinha, S ;

Thorsett, ED ;

John, V .

JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (02) :259-262

[29] β-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE [J].

Vassar, R ;

Bennett, BD ;

Babu-Khan, S ;

Kahn, S ;

Mendiaz, EA ;

Denis, P ;

Teplow, DB ;

Ross, S ;

Amarante, P ;

Loeloff, R ;

Luo, Y ;

Fisher, S ;

Fuller, L ;

Edenson, S ;

Lile, J ;

Jarosinski, MA ;

Biere, AL ;

Curran, E ;

Burgess, T ;

Louis, JC ;

Collins, F ;

Treanor, J ;

Rogers, G ;

Citron, M .

SCIENCE, 1999, 286 (5440) :735-741

[30] Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity [J].

Yan, RQ ;

Bienkowski, MJ ;

Shuck, ME ;

Miao, HY ;

Tory, MC ;

Pauley, AM ;

Brashler, JR ;

Stratman, NC ;

Mathews, WR ;

Buhl, AE ;

Carter, DB ;

Tomasselli, AG ;

Parodi, LA ;

Heinrikson, RL ;

Gurney, ME .

NATURE, 1999, 402 (6761) :533-537

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