title: Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators.
abstract: The metabotropic glutamate receptor subtype 5 has evolved into a promising target for the treatment of various diseases of the central nervous system, such as Fragile X and L-DOPA induced dyskinesia. One of the most advanced clinical compound is Novartis' AFQ-056 (Mavoglurant), which served us as a template for a scaffold hopping approach, generating a structurally diverse set of potent analogs. Both the limited aqueous solubility and the relatively poor metabolic stability of AFQ-056 were improved with hexahydrocyclopenta[c]pyrrole derivative 54a, which proved to be a valuable candidate for further development.
authors.affiliation: Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318 Frankfurt am Main, Germany. Electronic address: holger.kubas@merz.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Kubas
authors.forename: Udo
authors.initials: U
authors.lastname: Meyer
authors.forename: Mirko
authors.initials: M
authors.lastname: Hechenberger
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Klein
authors.forename: Patrick
authors.initials: P
authors.lastname: Plitt
authors.forename: Ronalds
authors.initials: R
authors.lastname: Zemribo
authors.forename: Harm W
authors.initials: HW
authors.lastname: Spexgoor
authors.forename: Sander G A
authors.initials: SG
authors.lastname: van Assema
authors.forename: Ulrich
authors.initials: U
authors.lastname: Abel
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D064529:Receptor, Metabotropic Glutamate 5 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D064529:Receptor, Metabotropic Glutamate 5; C581397:mavoglurant
keywords: AFQ-056; Allosteric modulator; CIZDIEPYKQXGQG-UHFFFAOYSA-N; Metabotropic glutamate receptor; OFNVYYXEOJUGRH-UHFFFAOYSA-N; SONLNLJEFBMKGV-UHFFFAOYSA-N; Scaffold hopping; mGluR5