Discovery of VU2957 (Valiglurax): An mGlu4 Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease

Joseph D Panarese; Darren W Engers; Yong-Jin Wu; Joanne J Bronson; John E Macor; Aspen Chun; Alice L Rodriguez; Andrew S Felts; Julie L Engers; Matthew T Loch; Kyle A Emmitte; Arlindo L Castelhano; Michael J Kates; Michael A Nader; Carrie K Jones; Anna L Blobaum; P Jeffrey Conn; Colleen M Niswender; Corey R Hopkins; Craig W Lindsley

doi:10.1021/acsmedchemlett.8b00426

Discovery of VU2957 (Valiglurax): An mGlu₄ Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease

ACS Med Chem Lett. 2018 Oct 16;10(3):255-260. doi: 10.1021/acsmedchemlett.8b00426. eCollection 2019 Mar 14.

Authors

Joseph D Panarese^{1

2}, Darren W Engers^{1

2}, Yong-Jin Wu³, Joanne J Bronson³, John E Macor³, Aspen Chun^{1

2}, Alice L Rodriguez^{1

2}, Andrew S Felts^{1

2}, Julie L Engers^{1

2}, Matthew T Loch^{1

2}, Kyle A Emmitte^{1

2}, Arlindo L Castelhano⁴, Michael J Kates⁴, Michael A Nader⁵, Carrie K Jones^{1

2

6}, Anna L Blobaum^{1

2}, P Jeffrey Conn^{1

2

6}, Colleen M Niswender^{1

2

6}, Corey R Hopkins^{1

2}, Craig W Lindsley^{1

2}

Affiliations

¹ Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
² Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
³ Bristol-Myers Squibb Co., Research & Development, 5 Research Parkway, Wallingford, Connecticut 06492 United States.
⁴ Davos Pharma, A Davos Chemical Company, 600 East Crescent Ave., Upper Saddle River, New Jersey 07458, United States.
⁵ Center for the Neurobiology of Addiction Treatment, Wake Forest School of Medicine, Medical Center Boulevard Winston-Salem, North Carolina 27157, United States.
⁶ Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.

Abstract

Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu₄ PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies. Based on its overall profile, VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson's disease.

Grants and funding

U54 HD083211/HD/NICHD NIH HHS/United States