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

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

ACS medicinal chemistry letters (2019-03-21)

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

PMID30891122

摘要

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.