Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3R Antagonism for Neurodegenerative Diseases
| Affiliation auteurs | !!!! Error affiliation !!!! |
| Titre | Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3R Antagonism for Neurodegenerative Diseases |
| Type de publication | Journal Article |
| Year of Publication | 2017 |
| Auteurs | Bautista-Aguilera OM, Hagenow S, Palomino-Antolin A, Farre-Alins V, Ismaili L, Joffrin P-L, Jimeno ML, Soukup O, Janockova J, Kalinowsky L, Proschak E, Iriepa I, Moraleda I, Schwed JS, Martinez ARomero, Lopez-Munoz F, Chioua M, Egea J, Ramsay RR, Marco-Contelles J, Stark H |
| Journal | ANGEWANDTE CHEMIE-INTERNATIONAL EDITION |
| Volume | 56 |
| Pagination | 12765-12769 |
| Date Published | OCT 2 |
| Type of Article | Article |
| ISSN | 1433-7851 |
| Mots-clés | antioxidants, drug design, inhibitors, multitarget drugs, neurological agents |
| Résumé | The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H-3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional invitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising invitro profile, contilisant (at 1mgkg(-1) i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits. |
| DOI | 10.1002/anie.201706072 |