Gamma Secretase Modulators Show Promise in Alzheimer's Disease Animal Model Efficacy Studies, According to Research Conducted by TorreyPines Therapeutics
Presented by Steven Wagner, Ph.D., the company's Chief Scientific Officer,at the recent Keystone Symposium on Alzheimer's Disease, data demonstratedthat GSMs provide a more selective mechanism than gamma secretase inhibitors(GSIs). The in vivo research involved internally discovered and optimizedcompounds that modulate the g-secretase complex without inhibiting itscatalytic activity. These GSMs appear to reduce the formation of the longerpathogenic Ab peptides (e.g, Ab42) and allow the g-secretase enzyme complex togenerate the shorter, less fibrillogenic Ab peptides such as Ab38 and Ab37 andto perform its other necessary functions.
"We have identified a series of GSM compounds that are intended tomodulate the enzyme's activity without preventing it from performing itsnormal functions," said Dr. Wagner. "These orally bio-available, smallmolecule GSMs appear to have addressed some of the pitfalls associated withthe GSI compounds, which have been associated with side effects. Thesignificance of our findings is that we may be able to selectively attenuatethe pathological functions of this enzyme complex without affecting the othercritical physiological functions it performs."
The major pathological hallmark of Alzheimer's disease is the abundance ofdeposits called neuritic plaques in key areas of the brain that control memoryand cognition. These neuritic plaques are largely comprised of aggregations offibrillar peptides referred to as amyloid b, or Ab peptides. Evidenceindicates that individuals genetically predisposed to early-onset forms ofAlzheimer's disease make a greater proportion of the longer Ab peptides,especially Ab42, relative to unaffected individuals. All of these Ab peptides,including the pathogenic Ab42 peptide, are derived via proteolysis from a muchlarger precursor molecule known as the amyloid b precursor protein (APP).
During normal catabolism, two crucial enzymes, or proteases, areresponsible for generating these Ab peptides from APP. The first enzyme, betasecretase (b-secretase), cuts the APP molecule into two major pieces comprisedof a soluble extracellular fragment and a membrane-associated fragment. Thesecond enzyme, gamma secretase (g-secretase), then cleaves the membrane-associated fragment into one of several different Ab peptides that vary inlength from 34 to 42 amino acids.
About TorreyPines Therapeutics
TorreyPines Therapeutics, Inc. is a biopharmaceutical company committed toproviding patients with better alternatives to existing therapies through theresearch, development and commercialization of small molecule compounds. Thecompany's goal is to develop versatile product candidates each capable oftreating a number of acute and chronic diseases and disorders such asmigraine, chronic pain, muscle spasticity and rigidity, xerostomia andcognitive disorders. The company is currently developing four productcandidates, two ionotropic glutamate receptor antagonists and two muscarinicreceptor agonists. Further information is available athttp://www.torreypinestherapeutics.com.
This press release contains forward-looking statements or predictions.Such forward-looking statements include, but are not limited to, statementsregarding the potential for GSMs as a treatment for Alzheimer's disease. Suchstatements are subject to numerous known and unknown risks, uncertainties andother factors, which may cause TorreyPines' actual results to be materiallydifferent from historical results or from any results expressed or implied bysuch forward-looking statements, including whether any preclinical studies orclinical trials conducted in the future, will prove successful, and ifsuccessful, whet
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