TPTX » Topics » Gamma-secretase Modulator Program

These excerpts taken from the TPTX 10-K filed Mar 31, 2008.

Gamma-secretase Modulator Program

        Our approach to Alzheimer's disease drug discovery is firmly rooted in the amyloid hypothesis. First generation approaches to lowering Aß42 focused on inhibiting, as opposed to modulating, the activity of a large, complex and essential enzyme called gamma-secretase that is involved in the production of Aß42. Gamma-secretase inhibitors have been associated with side effects presumably because they completely block the functioning of the enzyme towards other biologically important substrates.

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        We have identified two distinct series of second generation compounds that modulate the gamma-secretase enzyme as opposed to inhibiting it. These gamma-secretase modulators, or GSMs, reduce the brain levels of Aß42 while maintaining the overall balance of Aß in the brain. They do this by influencing the enzyme to make shorter, less toxic Aß peptides at the expense of the longer, toxic Aß42 peptide. Because GSM compounds allow the gamma-secretase enzyme to perform its normal functions on other substrates, it is believed they will likely not have some of the side effects associated with the first generation compounds that fully inhibited enzyme function.

        Our GSM compounds are small molecules that have been shown to penetrate the blood brain barrier upon chronic oral dosing in rodents. We believe that in the brain, they preferentially lower Aß42 levels by modulation of gamma-secretase.

Gamma-secretase Modulator Program



        Our approach to Alzheimer's disease drug discovery is firmly rooted in the amyloid hypothesis. First generation approaches to lowering
42 focused on inhibiting, as opposed to modulating, the activity of a large, complex and essential enzyme called gamma-secretase that is involved in the production of
42. Gamma-secretase inhibitors have been associated with side effects presumably because they completely block the functioning of the enzyme towards other biologically
important substrates.



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        We have identified two distinct series of second generation compounds that modulate the gamma-secretase enzyme as opposed to inhibiting it. These gamma-secretase modulators, or GSMs,
reduce the brain levels of Aß42 while maintaining the overall balance of Aß in the brain. They do this by influencing the enzyme to make shorter, less toxic
Aß peptides at the expense of the longer, toxic Aß42 peptide. Because GSM compounds allow the gamma-secretase enzyme to perform its normal functions on other
substrates, it is believed they will likely not have some of the side effects associated with the first generation compounds that fully inhibited enzyme function.



        Our
GSM compounds are small molecules that have been shown to penetrate the blood brain barrier upon chronic oral dosing in rodents. We believe that in the brain, they preferentially
lower Aß42 levels by modulation of gamma-secretase.




This excerpt taken from the TPTX 10-K filed Mar 29, 2007.

Gamma-secretase Modulator Program

Our approach to Alzheimer’s disease drug discovery is firmly rooted in the amyloid hypothesis. First generation approaches to lowering Aß42 focused on inhibiting, as opposed to modulating, the activity of a large, complex and essential enzyme called gamma-secretase that is involved in the production of Aß42. Gamma-secretase inhibitors have been associated with side effects presumably because they completely block the functioning of the enzyme.

We have identified two distinct series of second generation compounds that modulate, or influence, the gamma-secretase enzyme as opposed to inhibiting it. These gamma-secretase modulators, or GSMs, reduce the brain levels of Aß42 while maintaining the critical overall balance of Aß in the brain. They do this by influencing the enzyme to make shorter, less toxic Aß peptides at the expense of the longer, toxic Aß42 peptide. Because GSM compounds allow the gamma-secretase enzyme to perform its normal functions, they appear to have addressed some of the side effects associated with the first generation compounds that fully inhibited enzyme functioning.

Our GSM compounds are oral, small molecules that have been shown to penetrate the blood brain barrier upon chronic oral dosing in rodents. In the brain, they appear to preferentially lower Aβ42 levels by modulation of gamma-secretase.

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