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

Q3 · MEDICINE

Article

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

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.

01 Jan 2019·Bioorganic & medicinal chemistry lettersQ4 · MEDICINE

The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu4 PAM development candidate

Q4 · MEDICINE

Article

Author: Emmitte, Kyle A ; Hopkins, Corey R ; Niswender, Colleen M ; Gregro, Alison R ; Engers, Darren W ; Lindsley, Craig W ; Capstick, Rory A ; Macor, John E ; Jones, Carrie K ; Felts, Andrew S ; Westphal, Ryan ; Chun, Aspen ; Wieting, Joshua M ; Bronson, Joanne J ; Bender, Aaron M ; Guernon, Jason M ; Engers, Julie E ; Panarese, Joseph D ; Rodriguez, Alice L ; Blobaum, Anna L ; Conn, P Jeffrey ; Soars, Matthew ; Wu, Yong-Jin

This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu₄ positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Preclinical	United States	Vanderbilt University	16 Oct 2018

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