MEDI 245 |
| Alzheimer's disease (AD) is the most devastating human disease for which there is still no highly effective treatment. Currently available AD therapies only provide symptomatic treatment. The proposed causative role for Abeta40 and Abeta42 in the pathophysiology of AD has provided a rational strategy for the design of disease-modifying anti-AD drugs (DMAADs). By blocking the synthesis of these putative pathogenic peptides, it is hoped that the progression of AD will be slowed or prevented. We have focused our efforts on inhibition of gamma secretase, the final enzyme in the biosynthesis of Abeta40 and Abeta42 from APP. A caveat with this approach is that selectivity of gamma secretase inhibition of APP processing is required due to the importance of other gamma secretase substrates such as Notch in important physiological processes such as G.I. cell renewal. We have previously reported on the discovery of the Notch-sparing gamma secretase inhibitor (GSI) 5-chloro-N-[(1S)-2-ethyl-1-(hydroxymethyl)butyl]-2-thiophenesulfonamide (EC50Abeta40 and Abeta42 = 25 nM and 27 nM, respectively, EC50Notch= 246 nM) by optimization of an HTS lead. However, this compound shows limited oral activity in Tg2576 mice due to rapid in vivo metabolism. By identifying and blocking the sites of metabolism of this lead and related analogs we have designed and synthesized novel GSIs with potent, oral in vivo activity that also retain Notch-sparing selectivity. The evolution of this series of compounds will be discussed. |
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Abeta Production Inhibitors: Progress Toward a Clinical Test of the Amyloid Hypothesis
9:00 AM-12:00 PM, Wednesday, August 22, 2007 BCEC -- 210 B/C, Oral
Division of Medicinal Chemistry |