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.
Humphries
Paul S
PS
Pfizer Global R&D, Eastern Point Road, Groton, CT 06340, USA.
Benbow
John W
JW
Bonin
Paul D
PD
Boyer
David
D
Doran
Shawn D
SD
Frisbie
Richard K
RK
Piotrowski
David W
DW
Balan
Gayatri
G
Bechle
Bruce M
BM
Conn
Edward L
EL
Dirico
Kenneth J
KJ
Oliver
Robert M
RM
Soeller
Walter C
WC
Southers
James A
JA
Yang
Xiaojing
X
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