Synthesis and SAR of 1,2,3,4-tetrahydroisoquinolin-1-ones as novel G-protein-coupled receptor 40 (GPR40) antagonists.
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.
Pfizer Global R&D, Eastern Point Road, Groton, CT 06340, USA.
Paul S
PS
Humphries
John W
JW
Benbow
Paul D
PD
Bonin
David
D
Boyer
Shawn D
SD
Doran
Richard K
RK
Frisbie
David W
DW
Piotrowski
Gayatri
G
Balan
Bruce M
BM
Bechle
Edward L
EL
Conn
Kenneth J
KJ
Dirico
Robert M
RM
Oliver
Walter C
WC
Soeller
James A
JA
Southers
Xiaojing
X
Yang
D000284:Administration, Oral; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008657:Metabolic Clearance Rate; D008956:Models, Chemical; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*
C473034:FFAR1 protein, human; C473035:G-protein-coupled receptor 40, rat; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D044005:Tetrahydroisoquinolines