Assiut university researches
Design of Pentapeptidic BACE1 Inhibitors with
Carboxylic Acid Bioisosteres at P'1 and P4
Positions
Harichandra D. Tagad, Yoshio Hamada, Jeffrey-Tri Nguyen, Takashi
Hamada, Hamdy Abdel-Rahman*, Abdellah Yamani, Ayaka
Nagamine, Hayato Ikari, Naoto Igawa, Koushi Hidaka, Youhei
Sohma, Tooru Kimura, Yoshiaki Kiso
Abstract:
We previously reported potent BACE1 inhibitors KMI-420 and
KMI-570 possessing a hydroxymethylcarbonyl isostere as a
substrate transition-state mimic. Acidic moieties at the P'1
and P4 positions of KMI inhibitors are thought to be
unfavorable in terms of membrane permeability across the
blood-brain barrier. Herein, we replaced acidic moieties at the
P4 position with hydrogen bond accepting groups and acidic
moieties at the P'1 position with less acidic and similar
molecular-size moieties (carboxylic acid or tetrazole
bioisosteres). These inhibitors exhibited improved BACE1
inhibitory activities and a thorough quantitative structure–
activity relationship study was performed.
Published in:
Bioorg. Med. Chem.
doi:10.1016/j.bmc.2010.03.032,Vol.18,PP.3175-3186