Prevention of the formation of the beta-amyloid and specifically of the highly amyloidogenic isoform Abeta42 appears to be a prime drug target in the search for effective new Alzheimer drugs. The amyloid beta peptide is generated by cleavage of the amyloid precursor protein (APP) by the beta secretase at the beta-site of APP and by the multiprotein complex gamma secretase. Inhibitors of gamma secretase caused toxicity by the promiscuous substrate specificity and its role in the notch signalling pathway. Gamma secretase modulators seem to selectively inhibit the abeta42 production with several candidates in clinical development. Another strategy to avoid the gamma secretase inhibitor associated toxicity is the search for inhibitors of the beta-site APP-cleaving enzyme (BACE). In fact, there are about three times as many BACE inhibitors projects than gamma secretase modulators in R&D, albeit slightly behind the gamma secretase modulators. Many Big Pharma companies have programs for BACE inhibitors and gamma secretase modulators, but the early stage, technical difficulties and lack of clear clinical lead projects makes these targets also attractive for small biotech companies.

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