Selectivity to amyloid-β precursor protein cleavage provides hope against Alzheimer's

As the population in most industrialized nations ages, the development of disease-modifying agents against Alzheimer's disease (AD), the most common cause of dementia in the elderly, is one of the most important unmet medical needs in the world. Because of strong experimental support for amyloid-β (Aβ), a small peptide derived from the sequential cleavage of amyloid-β pre-cursor protein (APP) by BACE1 and γ-secretase, as the principle culprit in this devastating neurodegenerative disease, investigators focused efforts to develop com-pounds designed to inhibit the activity of γ-secretase in order to attenuate β-amyloidosis as a potential therapy for AD [1]. However, Eli Lilly and Company announced last year that it was halting the development of semagacestat, a first-in-man γ-secretase inhibitor [2,3]. Two ongoing phase III studies showed that treatments using semagacestat were associated with worsening of clinical measures of cognition and the ability to perform activities of daily living, as well as an increased risk of skin cancer. The exact molecular mechanisms underlying these adverse events remain unclear. However, semagacestat mechanistically inhibits not only γ-secretase to prevent Aβ production but also Notch, one of the most important physiological substrates for γ-secretase in vivo [4]; genetic and pharmacological studies in mice supported the notion that the inhibition of γ-secretase caused toxicities by impacting Notch signaling. The skin cancer risk was predicted from animal studies in which γ-secretase/Notch signaling was globally attenuated [5,6]. Thus, development of γ-secretase inhibitors/modulators that specifically inhibit the production of Aβ without influencing Notch activity is now necessary or mandatory as a treatment strategy for AD [2,7].In a recent paper, Basi and co-workers at Elan Pharmaceuticals report a preclinical study of two novel sulfonamide-type small molecules, ELN318463 and ELN475516 [8]. These compounds showed predominant inhibi