Scaffold hopping approach towards various AFQ-056 analogs as potent metabotropic glutamate receptor 5 negative allosteric modulators |
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| Authors: | Holger Kubas Udo Meyer Mirko Hechenberger Kai-Uwe Klein Patrick Plitt Ronalds Zemribo Harm W. Spexgoor Sander G.A. van Assema Ulrich Abel |
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| Affiliation: | 1. Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318 Frankfurt am Main, Germany;2. Institute of Organic Synthesis, Aizkraukles iela 21, Riga LV1006, Latvia;3. Mercachem B.V., Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands |
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| 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. |
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| Keywords: | Metabotropic glutamate receptor mGluR5 Allosteric modulator Scaffold hopping AFQ-056 |
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