Parallel synthesis of DAPT derivatives and their gamma-secretase-inhibitory activity

Toshiyuki Kan; Yusuke Tominari; Kentaro Rikimaru; Yuichi Morohashi; Hideaki Natsugari; Taisuke Tomita; Takeshi Iwatsubo; Tohru Fukuyama

doi:10.1016/j.bmcl.2004.01.067

Parallel synthesis of DAPT derivatives and their gamma-secretase-inhibitory activity

Bioorg Med Chem Lett. 2004 Apr 19;14(8):1983-5. doi: 10.1016/j.bmcl.2004.01.067.

Authors

Toshiyuki Kan¹, Yusuke Tominari, Kentaro Rikimaru, Yuichi Morohashi, Hideaki Natsugari, Taisuke Tomita, Takeshi Iwatsubo, Tohru Fukuyama

Affiliation

¹ Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

PMID: 15050642
DOI: 10.1016/j.bmcl.2004.01.067

Abstract

Parallel synthesis of the C-terminal-modified DAPT (1) derivatives was accomplished utilizing our novel resin 7. Condensation reaction of the N-acylamino acid 10 with the amines 11a-o proceeded smoothly to give the corresponding amides 6a-o without any epimerization. Among the analogues, the benzophenonemethyl amide derivative 6o showed 30 times more potent activity than the original DAPT (1).

Publication types

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

MeSH terms

Amides / chemical synthesis
Amides / pharmacology
Amyloid Precursor Protein Secretases
Benzophenones / chemical synthesis
Benzophenones / pharmacology
Dipeptides / chemical synthesis*
Dipeptides / pharmacology*
Endopeptidases / drug effects*
Endopeptidases / metabolism
Molecular Structure
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / pharmacology*

Substances

Amides
Benzophenones
Dipeptides
N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
N-(N-(3,5-difluorophenylacetyl)alanyl)phenylglycine 4-benzoylbenzyl amide
Protease Inhibitors
Amyloid Precursor Protein Secretases
Endopeptidases