MEDI 294 |
| Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the leading cause of dementia. Although the cause of AD is still unclear, deposition of b-amyloid peptide (Ab) in the brain is a hallmark of AD pathogenesis, and it is believed that therapeutic agents that lower Ab will be beneficial in the treatment of AD. Ab is produced from membrane-bound b-amyloid precursor protein (APP) by sequential proteolytic cleavage by b-secretase (BACE1) and g-secretase. Therefore, BACE1 is an attractive therapeutic target for AD. In this poster we will present novel pyridinylaminohydantoins as potent BACE1 inhibitors. X-ray crystal structure of pyridinylaminohydantoin compound in complex with BACE1 demonstrated that the aminohydantoin moiety interacts with the two aspartic acids in catalytic domain of BACE1, while pyridine nitrogen forms hydrogen bonding with Trp 76 at S2'. The optimization of the S3 pocket via parallel synthesis approach led to many very potent compounds. The synthesis, SAR and x-ray structure of the series will be presented. |
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Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster
Division of Medicinal Chemistry |