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.

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.

• Authors: Pedro M Garcia-Barrantes, Hyekyung P Cho, Adam M Metts, Anna L Blobaum, Colleen M Niswender, P Jeffrey Conn, Craig W Lindsley
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 26 Issue 3 Pg. 751-756 (Feb 01 2016) ISSN: 1464-3405 [Electronic] England
• PMID: 26778256 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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