KMI-358 and KMI-370, highly potent and small-sized BACE1 inhibitors containing phenylnorstatine.
Recently, we reported a novel substrate-based octapeptide BACE1 inhibitor KMI-008 containing hydroxymethylcarbonyl (HMC) isostere as a transition-state mimic. Using KMI-008 as a lead compound, a small-sized and highly potent BACE1 inhibitor KMI-370 (IC(50)=3.4 nM) was designed and synthesized.
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Tooru
T
Kimura
Daisuke
D
Shuto
Soko
S
Kasai
Ping
P
Liu
Koushi
K
Hidaka
Takashi
T
Hamada
Yoshio
Y
Hayashi
Chinatsu
C
Hattori
Masashi
M
Asai
Shinobu
S
Kitazume
Takaomi C
TC
Saido
Shoichi
S
Ishiura
Yoshiaki
Y
Kiso
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases; D006801:Humans; D010654:Phenylbutyrates / Q000737:chemistry* / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism
D010654:Phenylbutyrates; D011480:Protease Inhibitors; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human