Nanomolar-affinity, non-peptide oxytocin receptor antagonists.
Non-peptide antagonists of the peptide hormone oxytocin (OT) with nanomolar OT receptor affinities are described. These compounds incorporate novel amido- and amidoalkylcamphor variations to the lead structure L-366,509 (1) to achieve receptor affinity enhancements of 2-3 orders of magnitude over that compound. The new OT antagonist L-367,773 (35) is shown to be an orally bioavailable agent with good duration in vivo and to inhibit OT-stimulated uterine contractions effectively in several in vitro and in vivo models.
Evans
B E
BE
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
Lundell
G F
GF
Gilbert
K F
KF
Bock
M G
MG
Rittle
K E
KE
Carroll
L A
LA
Williams
P D
PD
Pawluczyk
J M
JM
Leighton
J L
JL
Young
M B
MB
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D005260:Female; D010121:Oxytocin / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D010879:Piperazines; D010880:Piperidines; D018045:Receptors, Oxytocin; D013141:Spiro Compounds; C077566:L 366509; D010121:Oxytocin