Discovery of small molecular (d)-leucinamides as potent, Notch-sparing γ-secretase modulators

•Aminoacid-based molecules as γ-secretase modulators were discovered.•Leucinamides modulating γ-secretase and ERK-mediated signaling were observed.•(R)-Epoxypropyl analog was the most potent, selective γ-secretase modulator.

Structural optimization of the prior lead 3 led to the small molecular (d)-leucinamides with potent modulating activity and Notch-sparing selectivity on the proteolytic processing of amyloid-β precursor proteins. The N-(R)-epoxypropyl analog 10c exhibited potent γ-secretase modulation compared to DAPT and showed substantial substrate selection for APP cleavage over Notch cleavage, while N-(2-fluoro)benzyl analog 10e showed the most potent γ-secretase inhibition with dull selectivity. The exceptional suppression of ERK-mediated activation suggested that these potent γ-secretase modulators may adapt an alternative pathway to prominently induce the differential inhibition of C99 cleavage by γ-secretase.

Graphical abstractAminoacid-based small molecules were designed for AD therapy. Leucinamide 10c was found to be a selective, potent γ-secretase modulator of proteolytic processing of APP and the analog 10e was most potent with dull selectivity. Figure optionsDownload full-size imageDownload as PowerPoint slide