Further optimization of the mGlu5 PAM clinical candidate VU0409551/JNJ-46778212: Progress and challenges towards a back-up compound

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3515-9. doi: 10.1016/j.bmcl.2015.06.096. Epub 2015 Jul 4.

Abstract

This Letter describes the progress and challenges in the continued optimization of the mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212. While many analogs addressed key areas for improvement, no one compound possessed the amalgamation of improvements needed within the (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanone scaffold to advance as a back-up clinical candidate. However, many analogs displayed excellent solubility and physiochemical properties, and were active in the amphetamine-induced hyperlocomotion (AHL) model. Moreover, the SAR was robust for this series of PAMs, and both polar and hydrogen-bond donors were found to be tolerated, leading to analogs with overall attractive profiles and good ligand efficiencies.

Keywords: Metabotropic glutamate receptor; Pharmacokinetics; Positive allosteric modulator (PAM); Schizophrenia; mGlu(5).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Drug Discovery
  • Humans
  • Molecular Structure
  • Receptor, Metabotropic Glutamate 5 / chemistry
  • Receptor, Metabotropic Glutamate 5 / therapeutic use*
  • Schizophrenia / genetics*
  • Structure-Activity Relationship

Substances

  • Receptor, Metabotropic Glutamate 5