Parallel synthesis of DAPT derivatives and their gamma-secretase-inhibitory activity.
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).
Kan
Toshiyuki
T
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Tominari
Yusuke
Y
Rikimaru
Kentaro
K
Morohashi
Yuichi
Y
Natsugari
Hideaki
H
Tomita
Taisuke
T
Iwatsubo
Takeshi
T
Fukuyama
Tohru
T
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases; D001577:Benzophenones / Q000138:chemical synthesis / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010450:Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*
D000577:Amides; D001577:Benzophenones; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C492933:N-(N-(3,5-difluorophenylacetyl)alanyl)phenylglycine 4-benzoylbenzyl amide; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases