KMI-008, a novel beta-secretase inhibitor containing a hydroxymethylcarbonyl isostere as a transition-state mimic: design and synthesis of substrate-based octapeptides.
A novel class of substrate-based beta-secretase (BACE1) inhibitors containing a hydroxymethylcarbonyl (HMC) isostere was designed and synthesized. Phenylnorstatine [(2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid; Pns] was an effective transition-state mimic at the P(1) position. Structure-activity relationships (SARs) of the P(3)-P(3)' positions of BACE1 inhibitors were studied.
Shuto
Daisuke
D
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Kasai
Soko
S
Kimura
Tooru
T
Liu
Ping
P
Hidaka
Koushi
K
Hamada
Takashi
T
Shibakawa
Saeko
S
Hayashi
Yoshio
Y
Hattori
Chinatsu
C
Szabo
Beata
B
Ishiura
Shoichi
S
Kiso
Yoshiaki
Y
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D015195:Drug Design; D010450:Endopeptidases / Q000378:metabolism*; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
C488219:KMI-008; D009842:Oligopeptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases