KMI-008, a novel beta-secretase inhibitor containing a hydroxymethylcarbonyl isostere as a transition-state mimic: design and synthesis of substrate-based octapeptides

Daisuke Shuto; Soko Kasai; Tooru Kimura; Ping Liu; Koushi Hidaka; Takashi Hamada; Saeko Shibakawa; Yoshio Hayashi; Chinatsu Hattori; Beata Szabo; Shoichi Ishiura; Yoshiaki Kiso

doi:10.1016/j.bmcl.2003.09.053

KMI-008, a novel beta-secretase inhibitor containing a hydroxymethylcarbonyl isostere as a transition-state mimic: design and synthesis of substrate-based octapeptides

Bioorg Med Chem Lett. 2003 Dec 15;13(24):4273-6. doi: 10.1016/j.bmcl.2003.09.053.

Authors

Daisuke Shuto¹, Soko Kasai, Tooru Kimura, Ping Liu, Koushi Hidaka, Takashi Hamada, Saeko Shibakawa, Yoshio Hayashi, Chinatsu Hattori, Beata Szabo, 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: 14643307
DOI: 10.1016/j.bmcl.2003.09.053

Abstract

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.

Publication types

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

MeSH terms

Amino Acid Sequence
Amyloid Precursor Protein Secretases
Drug Design
Endopeptidases / metabolism*
Models, Molecular
Oligopeptides / chemical synthesis
Oligopeptides / metabolism*
Oligopeptides / pharmacology*
Protease Inhibitors / chemical synthesis
Protease Inhibitors / pharmacology*
Protein Conformation
Structure-Activity Relationship

Substances

KMI-008
Oligopeptides
Protease Inhibitors
Amyloid Precursor Protein Secretases
Endopeptidases