Discovery and SAR study of a novel anti-Alzheimer compound family acting on APP

MEDI 291

Stéphane Burlet, stephane.burlet@ibl.fr1, Bénédicte Grasland, grasland@lille.inserm.fr2, Marie-Ange Debreu-Fontaine, marie-ange.debreu@ibl.fr1, Marie-Eve Grosjean, Marie-Eve.Grosjean@lille.inserm.fr2, André Delacourte, andre.delacourte@lille.inserm.fr2, and Patricia Melnyk, patricia.melnyk@ibl.fr1. (1) Team 3, UMR8161 CNRS, Lille1 University, Lille2 University, Pasteur Institute of Lille, 1, Rue du Pr Calmette, BP447, 59021 Lille, France, (2) Inserm U837, JPARC, Bâtiment Gérard Biserte, 1 place de Verdun, 59045 Lille, France
Alzheimer's disease (AD) is the most well known age related neurodegenerative dementia which is characterized by two main pathological hallmarks: intracellular neurofibrillary tangles and amyloid plaques (consisting of Abeta), a catabolic product of APP. This latter can be proceeded in two different ways. The first one leads to Abeta with the sequential action of beta and gamma secretase. In contrast, in the non-amyloidogenic pathway, APP is cut in the middle of Abeta sequence and releases metabolites that could have potential physiological and/or neurotrophic activities: sAPPalpha and AICD. Chloroquine was first reported to show the desired effects i.e decrease of Abeta and boost of AICD and sAPPalpha. Based on a screening oriented approach, a new family of compounds exhibiting the required effects but with powerful action was discovered. More than one hundred compounds was then synthesized and tested on cellular models then SAR studies lead to structural prerequisites for biological activity.
 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007