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.
Kimura
Tooru
T
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Shuto
Daisuke
D
Kasai
Soko
S
Liu
Ping
P
Hidaka
Koushi
K
Hamada
Takashi
T
Hayashi
Yoshio
Y
Hattori
Chinatsu
C
Asai
Masashi
M
Kitazume
Shinobu
S
Saido
Takaomi C
TC
Ishiura
Shoichi
S
Kiso
Yoshiaki
Y
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