First-Time Disclosure of CVN424, a Potent and Selective GPR6 Inverse Agonist for the Treatment of Parkinson’s Disease: Discovery, Pharmacological Validation, and Identification of a Clinical Candidate

Parkinson’s disease (PD) is
a chronic and progressive movement
disorder with the urgent unmet need for efficient symptomatic therapies
with fewer side effects. GPR6 is an orphan G-protein coupled receptor
(GPCR) with highly restricted expression in dopamine receptor D2-type
medium spiny neurons (MSNs) of the indirect pathway, a striatal brain
circuit which shows aberrant hyperactivity in PD patients. Potent
and selective GPR6 inverse agonists (IAG) were developed starting
from a low-potency screening hit (EC50 = 43 μM).
Herein, we describe the multiple parameter optimization that led to
the discovery of multiple nanomolar potent and selective GPR6 IAG,
including our clinical compound CVN424. GPR6 IAG reversed haloperidol-induced
catalepsy in rats and restored mobility in the bilateral 6-OHDA-lesioned
rat PD model demonstrating that inhibition of GPR6 activity in vivo normalizes activity in basal ganglia circuitry and
motor behavior. CVN424 is currently in clinical development to treat
motor symptoms in Parkinson’s disease.