|Author||Gay, Marion ♦ Evrard, Caroline ♦ Descamps, Florian ♦ Carato, Pascal ♦ Renault, Nicolas ♦ Coevoet, Mathilde ♦ Eddarkaoui, Sabiha ♦ Baud, Catherine ♦ Larchanché, Paul-Emmanuel ♦ Buée, Luc ♦ Bakali, Jamal El ♦ Vingtdeux, Valérie ♦ Sergeant, Nicolas ♦ Melnyk, Patricia|
|Source||Hyper Articles en Ligne (HAL)|
|Subject Keyword||chim ♦ sdv ♦ Chemical Sciences/Medicinal Chemistry ♦ Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology|
|Abstract||Dysregulation of the Amyloid Precursor Protein (APP) processing leading to toxic species of amyloid b peptides (Ab) is central to Alzheimer's disease (AD) etiology. Ab peptides are produced by sequential cleavage of APP by b-secretase (BACE-1) and g-secretase. Lysosomotropic agent, chloroquine (CQ), has been reported to inhibit Ab peptide production. However, this effect is accompanied by an inhibition of lysosome-mediated degradation pathways. Following on from the promising activity of two series of APP metabolism modulators derived from CQ, we sought to develop new series of compounds that would retain the inhibitory effects on Ab production without altering lysosome functions. Herein, we applied a ligand-based pharmacophore modeling approach coupled with de novo design that led to the discovery of a series of biaryl compounds. Structure-activity relationship studies revealed that minor modifications like replacing a piperidine moiety of compound 30 by a cyclohexyl (compound 31) allowed for the identification of compounds with the desired profile. Further studies have demonstrated that compounds 30 and 31 act through an indirect mechanism to inhibit b-secretase activity. This work shows that it is possible to dissociate the inhibitory effect on Ab peptide secretion of CQ-derived compounds from the lysosome-mediated degradation effect, providing a new profile of indirect b-secretase inhibitors.|
|Learning Resource Type||Article|
|Journal||European Journal of Medicinal Chemistry|
National Digital Library of India (NDLI) is a virtual repository of learning resources which is not just a repository with search/browse facilities but provides a host of services for the learner community. It is sponsored and mentored by Ministry of Education, Government of India, through its National Mission on Education through Information and Communication Technology (NMEICT). Filtered and federated searching is employed to facilitate focused searching so that learners can find the right resource with least effort and in minimum time. NDLI provides user group-specific services such as Examination Preparatory for School and College students and job aspirants. Services for Researchers and general learners are also provided. NDLI is designed to hold content of any language and provides interface support for 10 most widely used Indian languages. It is built to provide support for all academic levels including researchers and life-long learners, all disciplines, all popular forms of access devices and differently-abled learners. It is designed to enable people to learn and prepare from best practices from all over the world and to facilitate researchers to perform inter-linked exploration from multiple sources. It is developed, operated and maintained from Indian Institute of Technology Kharagpur.
NDLI is a conglomeration of freely available or institutionally contributed or donated or publisher managed contents. Almost all these contents are hosted and accessed from respective sources. The responsibility for authenticity, relevance, completeness, accuracy, reliability and suitability of these contents rests with the respective organization and NDLI has no responsibility or liability for these. Every effort is made to keep the NDLI portal up and running smoothly unless there are some unavoidable technical issues.
Ministry of Education, through its National Mission on Education through Information and Communication Technology (NMEICT), has sponsored and funded the National Digital Library of India (NDLI) project.
For any issue or feedback, please write to email@example.com