Discovery, Structure–Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4

• Published in: Journal of medicinal chemistry Vol. 60; no. 20; pp. 8515 - 8537
• Main Authors: Charvin, Delphine, Pomel, Vincent, Ortiz, Millan, Frauli, Mélanie, Scheffler, Sophie, Steinberg, Edith, Baron, Luc, Deshons, Laurène, Rudigier, Rachel, Thiarc, Delphine, Morice, Christophe, Manteau, Baptiste, Mayer, Stanislas, Graham, Danielle, Giethlen, Bruno, Brugger, Nadia, Hédou, Gaël, Conquet, François, Schann, Stephan
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26-10-2017
• Subjects: Allosteric Regulation; Animals; Antiparkinson Agents - pharmacokinetics; Antiparkinson Agents - pharmacology; Brain - drug effects; Chromatography, Liquid; Drug Discovery; HEK293 Cells; Humans; Mass Spectrometry; Mice; Proton Magnetic Resonance Spectroscopy; Rats; Receptors, Metabotropic Glutamate - drug effects; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00991

The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinson’s disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (−)-PHCCC. This work led to the identification of compound 40, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model. Moreover, we also describe the identification of compound 60 a close analogue of compound 40 with improved pharmacokinetic profile after oral administration. On the basis of its favorable and unique preclinical profile, compound 60 (PXT002331, now foliglurax) was nominated as a candidate for clinical development.