Design of pentapeptidic BACE1 inhibitors with carboxylic acid bioisosteres at P1' and P4 positions.
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 P(4) 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.
Tagad
Harichandra D
HD
Department of Medicinal Chemistry, Centre Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto 607-8412, Japan.
Hamada
Yoshio
Y
Nguyen
Jeffrey-Tri
JT
Hamada
Takashi
T
Abdel-Rahman
Hamdy
H
Yamani
Abdellah
A
Nagamine
Ayaka
A
Ikari
Hayato
H
Igawa
Naoto
N
Hidaka
Koushi
K
Sohma
Youhei
Y
Kimura
Tooru
T
Kiso
Yoshiaki
Y
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002264:Carboxylic Acids / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; C500029:KMI-420; C551971:KMI-570; D009842:Oligopeptides; D013844:Thiazoles; D014230:Triazoles; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human