Semagacestat (LY450139) is a small-molecule gamma-secretase inhibitor developed primarily for the treatment of Alzheimer's disease. It targets the enzyme gamma-secretase to reduce the production of amyloid-beta peptides, which are implicated in the formation of amyloid plaques in the brain, a key pathological feature of Alzheimer's.

Preclinical and early clinical studies showed that semagacestat could lower amyloid-beta levels in blood and cerebrospinal fluid. However, phase 3 clinical trials, conducted by Eli Lilly, were halted in 2010 due to lack of efficacy and serious adverse effects. These included an increased risk of non-melanoma skin cancers and worsening of cognitive function in patients. As a result, further development for Alzheimer's was discontinued in 2011.

Although not approved for clinical use, semagacestat remains a valuable research tool for studying gamma-secretase function and amyloid-beta production. Ongoing research explores its potential in other neurodegenerative disorders and informs the development of safer, more effective gamma-secretase modulators.