beta-Secretase inhibitors: modification at the P4 position and improvement of inhibitory activity in cultured cells.
Recently, we reported potent and small-sized beta-secretase (BACE1) inhibitors KMI-570 and KMI-684 in which we replaced carboxylic acid groups at the P(1)(') 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 P(4) 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.
Hamada
Yoshio
Y
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Japan.
Igawa
Naoto
N
Ikari
Hayato
H
Ziora
Zyta
Z
Nguyen
Jeffrey-Tri
JT
Yamani
Abdellah
A
Hidaka
Koushi
K
Kimura
Tooru
T
Saito
Kazuki
K
Hayashi
Yoshio
Y
Ebina
Maiko
M
Ishiura
Shoichi
S
Kiso
Yoshiaki
Y
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002264:Carboxylic Acids / Q000737:chemistry; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D010450:Endopeptidases / Q000737:chemistry*; D004952:Esters / Q000737:chemistry; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013777:Tetrazoles / Q000737:chemistry
D002264:Carboxylic Acids; D004952:Esters; D011480:Protease Inhibitors; D013777:Tetrazoles; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human