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P2‐402: A novel, highly specific glycogen synthase kinase‐3 inhibitor of marine origin
Author(s) -
Medina Miguel,
Martı́n-Aparicio Ester,
Pérez-Puerto Marı́a José,
Fuertes Ana,
Alonso Diana,
Alonso Mercedes,
Castro Ana,
Navarro-Rico Maria Luisa,
Orozco-Muñoz Leyre,
Monte-Millán Marı́a,
Martı́nez Ana
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.1481
Subject(s) - gsk 3 , glycogen synthase , kinase , biochemistry , phosphorylation , enzyme , chemistry , ic50 , serine , protein kinase a , gsk3b , mechanism of action , in vitro
study the mechanism of action of this family of compounds, we have observed that they do not show free radicals scavenger properties in vitro, nor they have any direct effect on the in vitro superoxide dismutase or catalase activities. Preliminary studies suggest that these compounds might act as potent Fe , but not Fe chelators. Interestingly, we have also shown that this family of compounds is able to significantly reduce A secretion in a number of APP-transfected cell lines. This effect correlates with an increase of sAPP , suggesting that is mediated by the activation of the -secretase. Whether all observed biological activities are mediated by the same mechanism of actions is unclear at the moment. An active medicinal chemistry program has been developed, leading to several naturally-derived, synthetic lead compounds with improved potencies and ADME properties. Some of these compounds are orally bioavailable and able to cross the blood brain barrier, and basic pharmacokinetics parameters have been determined in rodents. In vivo proof of efficacy studies are currently being carried out in different animal models of neurodegenerative diseases. Conclusions: This family of compounds could be of use in the preparation of medicaments for the treatment and/or prevention of oxidative stress-induced diseases or conditions, especially neurodegenerative diseases.