DAPT (GSI-IX)

DAPT, N-[N-(3,5-Difluorophenacetyl)-_L-alanyl]-S-phenylglycine t-butyl Ester, is a potent and specific inhibitor of  γ-secretase, a multimeric membrane protein complex that catalyzes proteolytic cleavage of amyloid precursor protein (APP) resulting in the accumulation of amyloi-β (Aβ) peptides which is associated with early on-set of familial Alzheimer’s disease (AD). It directly binds to the C-terminal fragment of the catalytic center of γ-secretase, presenilin (PS), especially within the transmenbrane domain 7 or more C-terminal region, resulting in the synthesis of a photoactivable DAPT derivative. Through oral administration, DAPT  dose-dependently reduced Aβ peptides levels in vivo in Plasma and cerebrospinal fluid in young (6 months old, plaque-free) and aged (17 months old, plaque-bearing) Tg2576 mice.

Reference

Thomas A. Lanz, Carol S. Himes, Giovanni Pallante, Lisa Adams, Shinji Yamazaki, Ben Amore, and Kalpana M. Merchant. The γ-secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-_L-alanyl]-S-phenylglycine t-butyl Ester reduces Aβ levels in vivo in plasma and cerebrospinal fluid in young (plague-free) and aged (plaque-bearing) Tg2576 mice. The Journal of Pharmacology and Experimental Therapeutics 2003: 305 (3) 864-871

Yuichi Morohashi, Toshiyuki Kan, Yusuke Tominari, Haruhiko Fuwa, Yumiko Okamura, Naoto Watanabe, Chihiro Sato, Hideaki Natsugari, Tohru Fukuyama, Takeshi Iwatsubo, and Taisuke Tomita. C-terminal fragment of presenilin is the molecular target of a dipeptidic γ-secretase-specific inhibitor DAPT (N-[N-(3,5-Difluorophenacetyl)-_L-alanyl]-S-phenylglycine t-butyl Ester). The Journal of Biological Chemistry 2006: 281(21) 14670-14676