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

Key Points

To identify and characterize a potent, selective, and orally bioavailable mGlu4 positive allosteric modulator suitable as a preclinical development candidate for Parkinson's disease.
Evaluated the in vitro selectivity, potency, and cross-species in vivo drug metabolism and pharmacokinetics (DMPK) of VU2957 (Valiglurax).
Formulated VU2957 as a spray-dried dispersion (SDD) to support investigational new drug (IND)-enabling toxicology assessments.
VU2957 demonstrated high potency, selectivity, central nervous system penetration, and oral bioavailability alongside favorable DMPK properties across species.
The spray-dried dispersion formulation achieved exposure profiles necessary to advance the compound as a preclinical candidate for Parkinson's disease treatment.

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Implication

Preclinical study reveals the oral bioavailability and brain penetrance of mGlu4 modulator VU2957 across species, highlighting its therapeutic potential for Parkinson's disease.

Abstract

Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu 4 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.

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Panarese et al. (2018) studied this question.

synapsesocial.com/papers/6aa910f853e0ff3c525126b4 https://doi.org/10.1021/acsmedchemlett.8b00426

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

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Cite This Study

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

Key Points

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Implication

Abstract

Discussion

Cite This Study

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