1.
Bioorg Med Chem Lett
; 22(23): 7223-6, 2012 Dec 01.
Article
in English
| MEDLINE
| ID: mdl-23084894
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.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemistry , Pyrimidinones/chemistry , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Thiophenes/chemistry , Administration, Oral , Animals , Chronic Pain/drug therapy , Disease Models, Animal , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Pyrimidinones/chemical synthesis , Pyrimidinones/therapeutic use , Rats , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/therapeutic use
2.
Bioorg Med Chem Lett
; 22(4): 1575-8, 2012 Feb 15.
Article
in English
| MEDLINE
| ID: mdl-22266036
ABSTRACT
A series of fused tricyclic mGluR1 antagonists containing a pyridone ring were synthesized. In vitro, these antagonists were potent against both human and rat isozymes, as well as selective for inhibiting mGluR1 over mGluR5. When dosed orally, several examples were active in vivo in a rat SNL test.