The outcomes of the clinical trials of the γ-secretase inhibitor Semagacestat 
(LY-450139) and the γ-secretase modulator (GSM) Tarenflurbil were disappointing, 
but may not represent the end of the γ-secretase era. γ-Secretase modulators, by 
definition, only block the γ-secretase cleavage of amyloid-β protein precursor 
(AβPP) to generate the longer, 42-residue amyloid-β (Aβ42) without changing the 
production of total Aβ. The first generation GSMs were shown to block Aβ42 
generation while increasing Aβ38. The non-steroidal anti-inflammatory drug, 
Tarenflurbil, binds to AβPP and shifts the cleavage site from Aβ42 to Aβ38. In 
addition, Tarenflurbil does not affect the γ-secretase cleavage of Notch. Even 
before the failed clinical trials of Tarenflurbil, second generation GSMs had 
emerged, and some of these GSMs interact with presenilin, which carries the 
active site of the γ-secretase. While second generation GSMs are 
pharmacologically superior to first generation GSMs, in vivo Aβ profiles 
(decreased levels of Aβ38, Aβ40, and Aβ42) in animals treated with potent GSMs 
are strikingly different from those in cultured cells. Thus, the unique 
pharmacologic properties of new GSMs and their mechanisms of action need to be 
elucidated in order to avoid the fate of Tarenflurbil. It is critical to 
understand how GSMs shift the "end" in vivo, i.e., shifting the γ-secretase 
cleavage at the C-terminal end of Aβ. In view of the myriad effects of candidate 
GSMs on Aβ production in cells and animals, drug development would benefit from 
better definition of the target-GSM interaction and physiological function of 
shorter Aβ peptides.