Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 2: 4-thiopyridyl acetophenones as non-tetrazole containing mGlu2 receptor potentiators

Anthony B Pinkerton; Rowena V Cube; John H Hutchinson; Joyce K James; Michael F Gardner; Hervé Schaffhauser; Blake A Rowe; Lorrie P Daggett; Jean-Michel Vernier

doi:10.1016/j.bmcl.2004.09.028

Allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2). Part 2: 4-thiopyridyl acetophenones as non-tetrazole containing mGlu2 receptor potentiators

Bioorg Med Chem Lett. 2004 Dec 6;14(23):5867-72. doi: 10.1016/j.bmcl.2004.09.028.

Authors

Anthony B Pinkerton¹, Rowena V Cube, John H Hutchinson, Joyce K James, Michael F Gardner, Hervé Schaffhauser, Blake A Rowe, Lorrie P Daggett, Jean-Michel Vernier

Affiliation

¹ Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. [email protected]

PMID: 15501058
DOI: 10.1016/j.bmcl.2004.09.028

Abstract

We have identified and synthesized a series of 4-thiopyridyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward replacement of the tetrazole in the initial lead led to the discovery of 16 (EC(50)=340 nM), which showed improved brain penetration over the initial lead.

MeSH terms

Acetophenones / chemistry
Acetophenones / metabolism*
Allosteric Regulation / physiology
Animals
Brain / metabolism
Cell Line
Humans
Protein Binding / physiology
Pyridines / chemistry*
Pyridines / metabolism*
Rats
Receptors, Metabotropic Glutamate / agonists
Receptors, Metabotropic Glutamate / metabolism*
Structure-Activity Relationship
Tetrazoles

Substances

Acetophenones
Pyridines
Receptors, Metabotropic Glutamate
Tetrazoles
metabotropic glutamate receptor 2