Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

  • Bioorg Med Chem Lett. 2019 Jan 1;29(1):47-50. doi: 10.1016/j.bmcl.2018.11.017.
Andrew S Felts  1 ,  Katrina A Bollinger  1 ,  Christopher J Brassard  1 ,  Alice L Rodriguez  1 ,  Ryan D Morrison  1 ,  J Scott Daniels  1 ,  Anna L Blobaum  1 ,  Colleen M Niswender  2 ,  Carrie K Jones  2 ,  P Jeffrey Conn  2 ,  Kyle A Emmitte  3 ,  Craig W Lindsley  4
Affiliations
  • 1. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 3. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected].
  • 4. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, 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: 30446311 DOI: 10.1016/j.bmcl.2018.11.017
Abstract

This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp3 character, uniform CYP450-mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand.

Keywords
CNS; Metabotropic glutamate receptor; Negative allosteric modulator (NAM); Structure-Activity Relationship (SAR); mGlu(5).
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