beta-Secretase inhibitors: Modification at the P-4 position and improvement of inhibitory activity in cultured cells

Hamada, Yoshio, Igawa, Naoto, Ikari, Hayato, Ziora, Zyta, Nguyen, Jeffrey-Tri, Yamani, Abdellah, Hidaka, Koushi, Kimura, Tooru, Saito, Kazuki, Hayashi, Yoshio, Ebina, Maiko, Ishiura, Shoichi and Kiso, Yoshiaki (2006) beta-Secretase inhibitors: Modification at the P-4 position and improvement of inhibitory activity in cultured cells. Bioorganic and Medicinal Chemistry Letters, 16 16: 4354-4359. doi:10.1016/j.bmcl.2006.05.046


Author Hamada, Yoshio
Igawa, Naoto
Ikari, Hayato
Ziora, Zyta
Nguyen, Jeffrey-Tri
Yamani, Abdellah
Hidaka, Koushi
Kimura, Tooru
Saito, Kazuki
Hayashi, Yoshio
Ebina, Maiko
Ishiura, Shoichi
Kiso, Yoshiaki
Title beta-Secretase inhibitors: Modification at the P-4 position and improvement of inhibitory activity in cultured cells
Formatted title
β-Secretase inhibitors: Modification at the P4 position and improvement of inhibitory activity in cultured cells
Journal name Bioorganic and Medicinal Chemistry Letters   Check publisher's open access policy
ISSN 0960-894X
1464-3405
Publication date 2006-08-15
Sub-type Article (original research)
DOI 10.1016/j.bmcl.2006.05.046
Volume 16
Issue 16
Start page 4354
End page 4359
Total pages 6
Place of publication East Park, Kidlington, Oxford, U.K.
Publisher Pergamon
Language eng
Formatted abstract
Recently, we reported potent and small-sized β-secretase (BACE1) inhibitors KMI-570 and KMI-684 in which we replaced carboxylic acid groups at the P1′ position of KMI-420 and KMI-429, respectively, with tetrazole derivatives as carboxylic acid bioisosteres. These modifications improved significantly BACE1 inhibitory activity and chemical stability. In this study, the acidic tetrazole ring of the P4 position of KMI-420 and KMI-570, respectively, was replaced with various hydrogen bond acceptor groups. We found BACE1 inhibitor KMI-574 that exhibited potent inhibitory activity in cultured cells as well as in vitro enzymatic assay.
Keyword Alzheimer’s disease
BACE1 inhibitor
Cultured cells
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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Created: Thu, 24 Mar 2011, 12:16:21 EST by Dr Zyta Ziora on behalf of Institute for Molecular Bioscience