TY - JOUR
T1 - Development of proneurogenic, neuroprotective small molecules
AU - MacMillan, Karen S.
AU - Naidoo, Jacinth
AU - Liang, Jue
AU - Melito, Lisa
AU - Williams, Noelle S.
AU - Morlock, Lorraine
AU - Huntington, Paula J.
AU - Estill, Sandi Jo
AU - Longgood, Jamie
AU - Becker, Ginger L.
AU - McKnight, Steven L.
AU - Pieper, Andrew A.
AU - De Brabander, Jef K.
AU - Ready, Joseph M.
PY - 2011/2/9
Y1 - 2011/2/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79551705492&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79551705492&partnerID=8YFLogxK
U2 - 10.1021/ja108211m
DO - 10.1021/ja108211m
M3 - Article
C2 - 21210688
AN - SCOPUS:79551705492
SN - 0002-7863
VL - 133
SP - 1428
EP - 1437
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 5
ER -