KMI-358 and KMI-370, highly potent and small-sized BACE1 inhibitors containing phenylnorstatine

Tooru Kimura; Daisuke Shuto; Soko Kasai; Ping Liu; Koushi Hidaka; Takashi Hamada; Yoshio Hayashi; Chinatsu Hattori; Masashi Asai; Shinobu Kitazume; Takaomi C Saido; Shoichi Ishiura; Yoshiaki Kiso

doi:10.1016/j.bmcl.2003.12.088

KMI-358 and KMI-370, highly potent and small-sized BACE1 inhibitors containing phenylnorstatine

Bioorg Med Chem Lett. 2004 Mar 22;14(6):1527-31. doi: 10.1016/j.bmcl.2003.12.088.

Authors

Tooru Kimura¹, Daisuke Shuto, Soko Kasai, Ping Liu, Koushi Hidaka, Takashi Hamada, Yoshio Hayashi, Chinatsu Hattori, Masashi Asai, Shinobu Kitazume, Takaomi C Saido, Shoichi Ishiura, Yoshiaki Kiso

Affiliation

¹ Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.

PMID: 15006396
DOI: 10.1016/j.bmcl.2003.12.088

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / metabolism
Cell Line
Dose-Response Relationship, Drug
Endopeptidases
Humans
Phenylbutyrates / chemistry*
Phenylbutyrates / metabolism
Protease Inhibitors / chemistry*
Protease Inhibitors / metabolism

Substances

Phenylbutyrates
Protease Inhibitors
3-amino-2-hydroxy-4-phenylbutanoic acid
Amyloid Precursor Protein Secretases
Endopeptidases
Aspartic Acid Endopeptidases
BACE1 protein, human