Discovery of VU2957 (Valiglurax): An mGlu(4) Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson's Disease

Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mG1u4 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...

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Published inACS medicinal chemistry letters Vol. 10; no. 3; pp. 255 - 260
Main Authors Panarese, Joseph D., Engers, Darren W., Wu, Yong-Jin, Bronson, Joanne J., Macor, John E., Chun, Aspen, Rodriguez, Alice L., Felts, Andrew S., Engers, Julie L., Loch, Matthew T., Emmitte, Kyle A., Castelhano, Arlindo L., Kates, Michael J., Nader, Michael A., Jones, Carrie K., Blobaurn, Anna L., Conn, P. Jeffrey, Niswender, Colleen M., Hopkins, Corey R., Lindsley, Craig W.
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 01.03.2019
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
RODENT MODELS
metabotropic glutamate receptor 4 (mGlu)
Parkinson's disease
SERIES
MGLUR4
VU0418506
Positive allosteric modulator (PAM)
GLUTAMATE-RECEPTOR 4
BASAL GANGLIA
L-DOPA
RECENT PROGRESS
VU2957
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Summary:Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mG1u4 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.
Bibliography:NIH RePORTER
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.8b00426