Abstract
High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
-
Administration, Oral
-
Animals
-
Chronic Pain / drug therapy
-
Disease Models, Animal
-
Heterocyclic Compounds, 3-Ring / chemical synthesis
-
Heterocyclic Compounds, 3-Ring / chemistry*
-
Heterocyclic Compounds, 3-Ring / therapeutic use
-
Humans
-
Pyrimidinones / chemical synthesis
-
Pyrimidinones / chemistry*
-
Pyrimidinones / therapeutic use
-
Rats
-
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
-
Receptors, Metabotropic Glutamate / metabolism
-
Structure-Activity Relationship
-
Thiophenes / chemical synthesis
-
Thiophenes / chemistry*
-
Thiophenes / therapeutic use
Substances
-
Heterocyclic Compounds, 3-Ring
-
Pyrimidinones
-
Receptors, Metabotropic Glutamate
-
Thiophenes
-
metabotropic glutamate receptor type 1