Synthesis and biological evaluation of novel indoloazepine derivatives as non-peptide vasopressin V2 receptor antagonists.
A series of novel 3,4,5,6-tetrahydro-1H-azepino[4,3,2-cd]indoles was synthesized and tested for vasopressin receptor antagonist activity. We identified compounds with high affinity for the human V2 receptor and good selectivity over the human V1a receptor. Compound 6c bound to V2 receptors with an IC(50) value of 20 nM, had >100-fold selectivity over V1a receptors, and inhibited cAMP formation in a cellular V2 functional assay with an IC(50) value of 70 nM.
Matthews
Jay M
JM
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. jmatthew@prius.jnj.com
Greco
Michael N
MN
Hecker
Leonard R
LR
Hoekstra
William J
WJ
Andrade-Gordon
Patricia
P
de Garavilla
Lawrence
L
Demarest
Keith T
KT
Ericson
Eric
E
Gunnet
Joseph W
JW
Hageman
William
W
Look
Richard
R
Moore
John B
JB
Maryanoff
Bruce E
BE
D065092:Antidiuretic Hormone Receptor Antagonists; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D020128:Inhibitory Concentration 50; D011869:Radioligand Assay; D017483:Receptors, Vasopressin / Q000235:genetics; D013329:Structure-Activity Relationship; D014162:Transfection
D065092:Antidiuretic Hormone Receptor Antagonists; D001381:Azepines; D017483:Receptors, Vasopressin; D000242:Cyclic AMP