Gamma Secretase Modulators Show Promise in Alzheimer's Disease Animal Model Efficacy Studies, According to Research Conducted by TorreyPines Therapeutics

LA JOLLA, Calif., March 31, 2008 /PRNewswire/ -- Gamma secretase modulators (GSMs) have shown promise in Alzheimer's disease animal model efficacy studies, according to research conducted by TorreyPines Therapeutics, Inc. .

Presented by Steven Wagner, Ph.D., the company's Chief Scientific Officer, at the recent Keystone Symposium on Alzheimer's Disease, data demonstrated that GSMs provide a more selective mechanism than gamma secretase inhibitors (GSIs). The in vivo research involved internally discovered and optimized compounds that modulate the g-secretase complex without inhibiting its catalytic activity. These GSMs appear to reduce the formation of the longer pathogenic Ab peptides (e.g, Ab42) and allow the g-secretase enzyme complex to generate the shorter, less fibrillogenic Ab peptides such as Ab38 and Ab37 and to perform its other necessary functions.

"We have identified a series of GSM compounds that are intended to modulate the enzyme's activity without preventing it from performing its normal functions," said Dr. Wagner. "These orally bio-available, small molecule GSMs appear to have addressed some of the pitfalls associated with the GSI compounds, which have been associated with side effects. The significance of our findings is that we may be able to selectively attenuate the pathological functions of this enzyme complex without affecting the other critical physiological functions it performs."

The major pathological hallmark of Alzheimer's disease is the abundance of deposits called neuritic plaques in key areas of the brain that control memory and cognition. These neuritic plaques are largely comprised of aggregations of fibrillar peptides referred to as amyloid b, or Ab peptides. Evidence indicates that individuals genetically predisposed to early-onset forms of Alzheimer'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 much larger precursor molecule known as the amyloid b precursor protein (APP).

During normal catabolism, two crucial enzymes, or proteases, are responsible for generating these Ab peptides from APP. The first enzyme, beta secretase (b-secretase), cuts the APP molecule into two major pieces comprised of a soluble extracellular fragment and a membrane-associated fragment. The second enzyme, gamma secretase (g-secretase), then cleaves the membrane- associated fragment into one of several different Ab peptides that vary in length from 34 to 42 amino acids.

About TorreyPines Therapeutics

TorreyPines Therapeutics, Inc. is a biopharmaceutical company committed to providing patients with better alternatives to existing therapies through the research, development and commercialization of small molecule compounds. The company's goal is to develop versatile product candidates each capable of treating a number of acute and chronic diseases and disorders such as migraine, chronic pain, muscle spasticity and rigidity, xerostomia and cognitive disorders. The company is currently developing four product candidates, two ionotropic glutamate receptor antagonists and two muscarinic receptor agonists. Further information is available at http://www.torreypinestherapeutics.com.

This press release contains forward-looking statements or predictions. Such forward-looking statements include, but are not limited to, statements regarding the potential for GSMs as a treatment for Alzheimer's disease. Such statements are subject to numerous known and unknown risks, uncertainties and other factors, which may cause TorreyPines' actual results to be materially different from historical results or from any results expressed or implied by such forward-looking statements, including whether any preclinical studies or clinical trials conducted in the future, will prove successful, and if successful, whether the results can be replicated; or whether safety and efficacy profiles the GSMs will be established, or if established, will remain the same, be better or worse in future clinical trials, if anyThese and other risks which may cause results to differ are described in greater detail in the "Risk Factors" section of TorreyPines' annual report on Form 10-K for the year ended December 31, 2006 and TorreyPines other SEC reports. The forward-looking statements are based on current information that is likely to change and speak only as of the date hereof.

Posted: March 2008

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