2. Academic Validation
  3. 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

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.
Pedro M Garcia-Barrantes 1,  Hyekyung P Cho 2,  Adam M Metts 3,  Anna L Blobaum 1,  Colleen M Niswender 2,  P Jeffrey Conn 2,  Craig W Lindsley 4
Affiliations

Affiliations

  • 1 Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, 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.
  • 3 Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
  • 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. Electronic address: craig.lindsley@vanderbilt.edu.
PMID: 26778256 DOI: 10.1016/j.bmcl.2015.12.104
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).

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