Current Topics in Medicinal Chemistry - Volume 8, Issue 1, 2008

Alzheimer's disease (AD) is the most common cause of dementia. According to the so called “amyloid hypothesis”, the oligomeric forms of a 40-42 aminoacid peptide known as β-amyloid (Aβ), is the main cause of neuronal death in AD. Aβ is the metabolite of a large transmembrane protein called amyloid precursor protein (APP). The last metabolic step that generates Aβ involves the enzymatic intramembrane cleavage of A Read More

γ-Secretase proteolyzes a variety of membrane-associated fragments derived from type I integral membrane proteins, including the amyloid β-protein precursor, involved in Alzheimer's disease, and the Notch receptor, critical for cellular differentiation. This protease is composed of four integral membrane proteins: presenilin, nicastrin, Aph-1 and Pen-2. Assembly of these four components leads to presenilin autoproteoly Read More

γ-secretase is an intramembranous protein complex that cleaves many type-I membrane proteins, including the Notch receptor and the β-amyloid precursor protein (APP). Interest in γ-secretase comes, in part, from the fact that this multiprotein complex is responsible for the cleavage of APP that generates the amyloid-β peptide (Aβ), one of the primary components of amyloid plaques in Alzheimer's disease (AD). Over the last Read More

Aβ 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, γ-secretase inhibitors are being actively pursued as potential AD therapeutics to reduce Aβ formation. This manuscript reviews recent progress in the medicinal chemistry of three major cl Read More

The genetics of Alzheimer's disease (AD) implies that restoring non-pathological levels or ratios of different amyloid-β (Aβ) peptide species in the brain could prevent the onset or delay the progression of this neurodegenerative disease. In particular, a selective reduction of the longer Aβ(1-42) peptide which is widely believed to be causative of AD is currently seen as an attractive approach for a disease-modifying therapy. Base Read More

γ-Secretase modulation holds the promise for the development of a disease-modifying therapy for Alzheimer's disease (AD). This novel concept of manipulating the cleavage specificity of the γ-secretase enzyme by pharmacological means implies that steady state levels of the potentially disease-causing amyloid-β(1-42) peptide can be lowered without the undesired side effects associated with full inhibition of this aspartyl- Read More

Genetic and biochemical evidence continues to implicate the production and accumulation of the Aβ42 peptide as the causative factor in Alzheimer's disease (AD). Thus, a variety of strategies have been developed to decrease the production and/or aggregation of this peptide, which may be clinically useful for the treatment of this devastating disorder. Recently, the discovery that some non-steroidal anti-inflammatory Read More

According to the β-amyloid (Aβ) hypothesis, compounds that inhibit γ-secretase, the pivotal enzyme that generates Aβ, are potential therapeutics for Alzheimer's disease (AD). Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, scanty data are available on the effects of these co Read More

Overcoming Resistance. Over four years ago, on May 2, 2003, the FDA approved Iressa™ (gefitinib) by AstraZeneca for the treatment of non-small cell lung cancer (NSCLC) in patients that failed to respond to two other types of chemotherapy. The potential therapeutic benefit of Iressa™, a once-daily tablet, was obvious, as the drug elicited an objective response and was well-tolerated in Phase II trials. The subsequent Phase Read More