2. Academic Validation
  3. Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators

Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators

  • Bioorg Med Chem Lett. 2013 Dec 1;23(23):6370-6. doi: 10.1016/j.bmcl.2013.09.059.
Holger Kubas 1,  Udo Meyer,  Mirko Hechenberger,  Kai-Uwe Klein,  Patrick Plitt,  Ronalds Zemribo,  Harm W Spexgoor,  Sander G A van Assema,  Ulrich Abel
Affiliations

Affiliation

  • 1 Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318 Frankfurt am Main, Germany. Electronic address: holger.kubas@merz.de.
PMID: 24125886 DOI: 10.1016/j.bmcl.2013.09.059
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.

Keywords

AFQ-056; Allosteric modulator; CIZDIEPYKQXGQG-UHFFFAOYSA-N; Metabotropic glutamate receptor; OFNVYYXEOJUGRH-UHFFFAOYSA-N; SONLNLJEFBMKGV-UHFFFAOYSA-N; Scaffold hopping; mGluR5.

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