Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor

被引：131

作者：

Cumming, Jared N. ^{[1
]}

Smith, Elizabeth M. ^{[1
]}

Wang, Lingyan ^{[1
]}

Misiaszek, Jeffrey ^{[1
]}

Durkin, James ^{[1
]}

Pan, Jianping ^{[1
]}

Iserloh, Ulrich ^{[1
]}

Wu, Yusheng ^{[1
]}

Zhu, Zhaoning ^{[1
]}

Strickland, Corey ^{[1
]}

Voigt, Johannes ^{[1
]}

Chen, Xia ^{[1
]}

Kennedy, Matthew E. ^{[1
]}

Kuvelkar, Reshma ^{[1
]}

Hyde, Lynn A. ^{[1
]}

Cox, Kathleen ^{[1
]}

Favreau, Leonard ^{[1
]}

Czarniecki, Michael F. ^{[1
]}

Greenlee, William J. ^{[1
]}

McKittrick, Brian A. ^{[1
]}

Parker, Eric M. ^{[1
]}

Stamford, Andrew W. ^{[1
]}

机构：

[1] Merck Res Labs, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 07期

关键词：

BACE; beta-Secretase; Alzheimer's disease; Iminohydantoin; In vivo; AMYLOID PRECURSOR PROTEIN; BETA-SECRETASE; ALZHEIMERS-DISEASE; POTENT; SITE; AMINOHYDANTOINS; MYELINATION; BRAIN; PART; MICE;

D O I：

10.1016/j.bmcl.2012.02.013

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Ab following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：2444 / 2449

页数：6

共 33 条

[1]

Design, Synthesis, and Qualitative Structure-Activity Evaluations of Novel β-Secretase Inhibitors as Potential Alzheimer's Drug Leads [J].

Al-Tel, Taleb H. ;

Semreen, Mohammad H. ;

Al-Qawasmeh, Raed A. ;

Schmidt, Marco F. ;

El-Awadi, Raafat ;

Ardah, Mustafa ;

Zaarour, Rania ;

Rao, Shashidhar N. ;

El-Agnaf, Omar .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (24) :8373-8385

[2]

[Anonymous], JAG VERS 5 5

[3]

Alzheimer's disease [J].

Scheltens, Philip ;

De Strooper, Bart ;

Kivipelto, Miia ;

Holstege, Henne ;

Chetelat, Gael ;

Teunissen, Charlotte E. ;

Cummings, Jeffrey ;

van der Flier, Wiesje M. .

LANCET, 2021, 397 (10284) :1577-1590

[4]

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

[5]

The secretases: enzymes with therapeutic potential in Alzheimer disease [J].

De Strooper, Bart ;

Vassar, Robert ;

Golde, Todd .

NATURE REVIEWS NEUROLOGY, 2010, 6 (02) :99-107

[6]

Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice [J].

Dominguez, D ;

Tournoy, J ;

Hartmann, D ;

Huth, T ;

Cryns, K ;

Deforce, S ;

Serneels, L ;

Camacho, IE ;

Marjaux, E ;

Craessaerts, K ;

Roebroek, AJM ;

Schwake, M ;

D'Hooge, R ;

Bach, P ;

Kalinke, U ;

Moechars, D ;

Alzheimer, C ;

Reiss, K ;

Saftig, P ;

De Strooper, B .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (35) :30797-30806

[7]

Bace2 Is a β Cell-Enriched Protease that Regulates Pancreatic β Cell Function and Mass [J].

Esterhazy, Daria ;

Stuetzer, Ina ;

Wang, Haiyan ;

Rechsteiner, Markus P. ;

Beauchamp, Jeremy ;

Doebeli, Heinz ;

Hilpert, Hans ;

Matile, Hugues ;

Prummer, Michael ;

Schmidt, Alexander ;

Lieske, Nora ;

Boehm, Bernhard ;

Marselli, Lorella ;

Bosco, Domenico ;

Kerr-Conte, Julie ;

Aebersold, Ruedi ;

Spinas, Giatgen Andreia ;

Moch, Holger ;

Migliorini, Cristiano ;

Stoffel, Markus .

CELL METABOLISM, 2011, 14 (03) :365-377

[8]

Global prevalence of dementia: a Delphi consensus study [J].

Ferri, CP ;

Prince, M ;

Brayne, C ;

Brodaty, H ;

Fratiglioni, L ;

Ganguli, M ;

Hall, K ;

Hasegawa, K ;

Hendrie, H ;

Huang, YQ ;

Jorm, A ;

Mathers, C ;

Menezes, PR ;

Rimmer, E ;

Scazufca, M .

LANCET, 2005, 366 (9503) :2112-2117

[9]

Medicine - The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics [J].

Hardy, J ;

Selkoe, DJ .

SCIENCE, 2002, 297 (5580) :353-356

[10]

Antibodies against β-amyloid slow cognitive decline in Alzheimer's disease [J].

Hock, C ;

Konietzko, U ;

Streffer, JR ;

Tracy, J ;

Signorell, A ;

Müller-Tillmanns, B ;

Lemke, U ;

Henke, K ;

Moritz, E ;

Garcia, E ;

Wollmer, MA ;

Umbricht, D ;

de Quervain, DJF ;

Hofmann, M ;

Maddalena, A ;

Papassotiropoulos, A ;

Nitsch, RM .

NEURON, 2003, 38 (04) :547-554

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