期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 133, 期 5, 页码 1428-1437出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja108211m
关键词
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资金
- Hartwell Foundation
- Staglin Family Fund
- UT Southwestern High Risk/High Impact Research Fund
- National Alliance for Research on Schizophrenia and Depression
- Morton H. Meyerson Family Tzedakah Fund
- NIH [1R01 MH087986, 5DP1OD000276, RO1M-N59388, 5PO1CA95471]
- Simons Foundation
- Welch foundation [I-1612, I-1422]
Degeneration of the hippocampus is associated with Alzheimer's disease and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer's are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches. We discovered the first synthetic molecule, named P7C3, which protects newborn neurons from apopotic cell death, and thus promotes neurogenesis in mice and rats in the subgranular zone of the hippocampal dentate gyrus, the site of normal neurogenesis in adult mammals. We describe the results of a medicinal chemistry campaign to optimize the potency, toxicity profile, and stability of P7C3. Systematic variation of nearly every position of the lead compound revealed elements conducive toward increases in activity and regions subject to modification. We have discovered compounds that are orally available, nontoxic, stable in mice, rats, and cell culture, and capable of penetrating the blood brain barrier. The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photo-cross-linking.
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