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

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.