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

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

doi:10.1016/j.bmcl.2018.10.050

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

Bioorg Med Chem Lett. 2019 Jan 15;29(2):342-346. doi: 10.1016/j.bmcl.2018.10.050. Epub 2018 Nov 1.

Authors

Joseph D Panarese¹, Darren W Engers¹, Yong-Jin Wu², Jason M Guernon², Aspen Chun¹, Alison R Gregro¹, Aaron M Bender¹, Rory A Capstick¹, Joshua M Wieting¹, Joanne J Bronson², John E Macor², Ryan Westphal², Matthew Soars², Julie E Engers¹, Andrew S Felts¹, Alice L Rodriguez¹, Kyle A Emmitte¹, Carrie K Jones¹, Anna L Blobaum¹, P Jeffrey Conn³, Colleen M Niswender³, Corey R Hopkins⁴, Craig W Lindsley⁵

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
² Bristol-Myers Squibb Co., Research & Development, 5 Research Parkway, Wallingford, CT 06492 USA.
³ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁴ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected].
⁵ Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected].

PMID: 30503632
DOI: 10.1016/j.bmcl.2018.10.050

Abstract

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).

Keywords: Metabotropic glutamate receptor; Parkinson’s disease (PD); Positive allosteric modulator (PAM); Structure-activity relationship (SAR); mGlu(4).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Heterocyclic Compounds, 2-Ring / chemistry
Heterocyclic Compounds, 2-Ring / pharmacology*
Humans
Isoquinolines / chemistry
Isoquinolines / pharmacology*
Molecular Structure
Myotonin-Protein Kinase / antagonists & inhibitors*
Myotonin-Protein Kinase / metabolism
Receptors, Metabotropic Glutamate / metabolism*
Structure-Activity Relationship

Substances

DMPK protein, human
Heterocyclic Compounds, 2-Ring
Isoquinolines
Receptors, Metabotropic Glutamate
VU0652957
Myotonin-Protein Kinase