Recent Progress in the Medicinal Chemistry of γ-Secretase Inhibitors

Abstract

Abeta is implicated in the initiation and progression of Alzheimer's disease (AD) by the phenotypic analysis of mutations in three human genes that lead to inherited, early forms of AD and data from preclinical studies. Based on this evidence, gamma-secretase inhibitors are being actively pursued as potential AD therapeutics to reduce Abeta formation. This manuscript reviews recent progress in the medicinal chemistry of three major classes of gamma-secretase inhibitors: peptide isosteres, azepines, and sulfonamides. Peptide isosteres have been useful for demonstrating that presenilin is the catalytic subunit of gamma-secretase and probing the active site. The peptidic nature of these inhibitors has, however, interfered with their utility for in vivo studies. Instead, the pharmaceutical industry has focused on optimizing azepines and sulfonamides. Both azepines and sulfonamides bind to a common, allosteric site on presenilin that differs from the active site identified by the peptide isosteres. Significant progress in the optimization of both azepines and sulfonamides has led to compounds that inhibit brain Abeta synthesis in preclinical models and has culminated in the identification of gamma-secretase inhibitors, including LY-450139 and MK-0752, for human trials.

Blood-Borne Amyloid-β Dimer Correlates with Clinical Markers of Alzheimer's Disease

“…A number of potential AD therapeutic strategies targeting A␤ and its oligomers (so called disease-modifying drugs) are currently being investigated, including immunotherapy designed to promote A␤ clearance (Nicoll et al, 2006), secretase inhibitors, which prevent A␤ generation (Olson and Albright, 2008), scyllo-inositol, which is reported to inhibit toxic A␤ oligomers binding to membranes (Nitz et al, 2008), and PBT2-a second generation MPAC that inhibits the formation of toxic A␤ oligomers (Adlard et al, 2008). The assessment of outcomes of the clinical trials is often difficult to define as they rely on highly variable neuropsychometric tests.…”

Targeting Cancer Stem Cells with Small Molecules

“…Exploiting this, the g-secretase targeting drug MK-0752 inhibits NOTCH signaling in malignant tumors of the central nervous system, [41] which are typically refractory to conventional treatments. [41][42] Treatment of colon cancer cells with honokiol, a molecule based on a biphenolic scaffold, suppressed proliferation and colony formation. [43] Reduced numbers and sizes of spheroids were also observed, which was associated with reduced expression of the cancer stem cell marker protein DCLK1 (doublecortin like kinase 1) upon honokiol treatment.…”

Disposition and Metabolism of Semagacestat, a γ-Secretase Inhibitor, in Humans

“…Mutations in APP near cleavage sites resulting in the A␤ formation have been linked to AD in several families (Selkoe, 2001;Imbimbo, 2008). This observation suggests that a reduction in A␤ synthesis could slow the disease progression in patients with AD.Semagacestat, an azepine class ␥-secretase inhibitor, is one of a very few ␥-secretase inhibitors that have been advanced into clinical trials as potential disease-modifying agents for the treatment of AD (Olson and Albright, 2008). Semagacestat reduces the rate of formation of A␤ in whole cell assays, as well as in transgenic and nontransgenic mice, beagle dogs, and guinea pigs Hyslop et al, 2004;May et al, 2004;Lanz et al, 2006).…”