Lead optimization of the VU0486321 series of mGlu(1) PAMs. Part 2: SAR of alternative 3-methyl heterocycles and progress towards an in vivo tool

Bioorg Med Chem Lett. 2016 Feb 1;26(3):751-756. doi: 10.1016/j.bmcl.2015.12.104. Epub 2016 Jan 2.

Abstract

This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep and caveat-laden SAR plagues the series, but ultimately potent mGlu1 PAMs (EC50s ∼5 nM) have resulted with good DMPK properties (low intrinsic clearance, clean CYP profile, modest Fu) and CNS penetration (Kps 0.25-0.97), along with up to >450-fold selectivity versus mGlu4 and mGlu5.

Keywords: Metabotropic glutamate receptor; Positive allosteric modulator (PAM); Schizophrenia; Structure–Activity Relationship (SAR); mGlu(1).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Animals
  • Antipsychotic Agents / chemistry*
  • Antipsychotic Agents / pharmacokinetics
  • Antipsychotic Agents / therapeutic use
  • Coumarins / chemistry*
  • Coumarins / pharmacokinetics
  • Coumarins / therapeutic use
  • Furans / chemistry*
  • Furans / pharmacokinetics
  • Furans / therapeutic use
  • Half-Life
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / pharmacokinetics
  • Heterocyclic Compounds / therapeutic use
  • Humans
  • Protein Binding
  • Rats
  • Receptors, Metabotropic Glutamate / chemistry*
  • Receptors, Metabotropic Glutamate / metabolism
  • Schizophrenia / drug therapy
  • Structure-Activity Relationship

Substances

  • Antipsychotic Agents
  • Coumarins
  • Furans
  • Heterocyclic Compounds
  • Receptors, Metabotropic Glutamate
  • VU0486321