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

被引：15

作者：

Sun, Huikai ^{[1
]}

Monenschein, Holger ^{[1
]}

Schiffer, Hans H. ^{[1
]}

Reichard, Holly A. ^{[1
]}

Kikuchi, Shota ^{[1
]}

Hopkins, Maria ^{[1
]}

Macklin, Todd K. ^{[1
]}

Hitchcock, Stephen ^{[1
]}

Adams, Mark ^{[1
]}

Green, Jason ^{[1
]}

Brown, Jason ^{[1
]}

Murphy, Sean T. ^{[1
]}

Kaushal, Nidhi ^{[1
]}

Collia, Deanna R. ^{[1
]}

Moore, Steve ^{[1
]}

Ray, William J. ^{[1
]}

English, Nicole Marion ^{[1
]}

Carlton, Mark Beresford Lewis ^{[2
]}

Brice, Nicola L. ^{[2
]}

机构：

[1] Takeda Calif, San Diego, CA 92121 USA

[2] Cerevance Ltd, Cambridge, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 14期

关键词：

RECEPTOR; INHIBITION; MECHANISMS; DOPAMINE; LEVODOPA; LIGAND; NEURON; MOUSE;

D O I：

10.1021/acs.jmedchem.0c02081

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu M). 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.

引用

页码：9875 / 9890

页数：16