The Cerevance/Takeda GPR6 inverse agonist (CVN424) is an oral, once-daily clinical candidate in Ph. II for Parkinson’s disease after completing a Ph. I in healthy volunteers. Its >40 µM starting point was discovered through a 360k compound cell-based HTS targeting human GPR6 (an orphan GPCR). The molecule CVN424 is interesting because it is brain penetrant and orally available even with five rings and numerous polar atoms and metabolic soft spots. In vivo, CVN424 increases locomotor activity, reverses haloperidol induced catalepsy and restores mobility in a bilateral 6-OHDA lesion model of Parkinson’s disease. With its non-dopaminergic mechanism, CVN424 is a potential drug for treating the motor symptoms of PD with a reduced risk of adverse effects such as L-DOPA induced dyskinesias.