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

5 years ago

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

Edith Steinberg, Sophie Scheffler, Danielle Graham, Christophe Morice, Delphine Thiarc, Rachel Rudigier, Luc Baron, Mélanie Frauli, Nadia Brugger, Vincent Pomel, François Conquet, Gaël Hédou, Laurène Deshons, Stephan Schann, Stanislas Mayer, Bruno Giethlen, Delphine Charvin, Millan Ortiz, Baptiste Manteau

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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00991

DOI: 10.1021/acs.jmedchem.7b00991