Abstract
The development of a series of novel 1,2,3,4-tetrahydroisoquinolin-1-ones as antagonists of G protein-coupled receptor 40 (GPR40) is described. The synthesis, in vitro inhibitory values for GPR40, in vitro microsomal clearance and rat in vivo clearance data are discussed. Initial hits displayed high rat in vivo clearances that were higher than liver blood flow. Optimization of rat in vivo clearance was achieved and led to the identification of 15i, whose rat oral pharmacokinetic data is reported.
MeSH terms
-
Administration, Oral
-
Animals
-
Chemistry, Pharmaceutical / methods
-
Drug Design
-
Drug Evaluation, Preclinical
-
Humans
-
Inhibitory Concentration 50
-
Ligands
-
Metabolic Clearance Rate
-
Models, Chemical
-
Rats
-
Receptors, G-Protein-Coupled / antagonists & inhibitors*
-
Receptors, G-Protein-Coupled / chemistry*
-
Structure-Activity Relationship
-
Tetrahydroisoquinolines / chemical synthesis*
-
Tetrahydroisoquinolines / chemistry
-
Tetrahydroisoquinolines / pharmacokinetics*
Substances
-
FFAR1 protein, human
-
G-protein-coupled receptor 40, rat
-
Ligands
-
Receptors, G-Protein-Coupled
-
Tetrahydroisoquinolines