Design of pentapeptidic BACE1 inhibitors with carboxylic acid bioisosteres at P-1 ' and P-4 positions

作者：Tagad Harichandra D; Hamada Yoshio; Nguyen Jeffrey Tri; Hamada Takashi; Abdel Rahman Hamdy; Yamani Abdellah; Nagamine Ayaka; Ikari Hayato; Igawa Naoto; Hidaka Koushi; Sohma Youhei; Kimura Tooru; Kiso Yoshiaki^*

来源：Bioorganic & Medicinal Chemistry, 2010, 18(9): 3175-3186.

DOI：10.1016/j.bmc.2010.03.032

• Alzheimer disease
• beta-Secretase
• Inhibitors
• Bioisosteres
• Structure-activity relationship

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 P-4 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.

• 出版日期2010-5-1