γ-secretase inhibitors and modulators for the treatment of Alzheimer's disease: disappointments and hopes.

According to the � -amyloid (A� ) hypothesis, compounds that inhibit or modulate �� secretase, the pivotal en- zyme that generates A� , are potential therapeutics for Alzheimer's disease (AD). Studies in both transgenic and non- transgenic animal models of AD have indicated that �� secretase inhibitors, administered by the oral route, are able to lower brain Aconcentrations. However, scanty data are available on the effects of these compounds on brain Adeposi- tion after chronic administration. Behavioral studies are also scarce with only one study indicating positive cognitive ef- fects of a peptidomimetic compound acutely administered (DAPT). � -Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen and skin in experimental animals and in man. These toxic effects are likely due to inhibition of Notch cleavage, a transmembrane receptor involved in regulating cell-fate decisions. Some non-steroidal anti-inflammatory drugs (NSAIDs) and other small organic molecules have been found to modulate �� secretase shifting its cleavage activity from longer to shorter � -amyloid species without affecting Notch cleavage. Long-term histopa- thological and behavioral animal studies are available with these NSAIDs (mainly ibuprofen) but it is unclear if the ob- served in vivo effects on Abrain pathology and learning depend on their activity on � -secretase or on other biological targets. The most studied � -secretase inhibitor, semagacestat (LY-450139), was shown to dose-dependently decrease the generation of Ain the cerebrospinal fluid of healthy humans. Unfortuantely, two large Phase 3 clinical trials of sema- gacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of detrimental effects on cognition and functionality in patients receiving the drug compared to those receiving placebo. These detrimental ef- fects were mainly ascribed to the inhibition of Notch processing and to the accumulation of the neurotoxic precursor of A� (the carboxy-terminal fragment of APP, or CTF� ) resulting from the block of the � -secretase cleavage activity on APP. Two large Phase 3 studies in mild AD patients with tarenflurbil (R-flurbiprofen), a putative � -secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notch- sparing � -secretase inhbitors and more potent, more brain penetrant � -secretase modulators are being developed with the hope of overcoming the previous setbacks.