Nanomolar-affinity, non-peptide oxytocin receptor antagonists

• Published in: Journal of medicinal chemistry Vol. 36; no. 25; pp. 3993 - 4005
• Main Authors: Evans, Ben E, Lundell, George F, Gilbert, Kevin F, Bock, Mark G, Rittle, Kenneth E, Carroll, Leigh Anne, Williams, Peter D, Pawluczyk, Joseph M, Leighton, James L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.12.1993
• Subjects: Animals; Binding Sites - drug effects; Chemistry; Exact sciences and technology; Female; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Organic chemistry; Oxytocin - antagonists & inhibitors; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Piperidines - chemistry; Piperidines - pharmacology; Preparations and properties; Rats; Receptors, Oxytocin - antagonists & inhibitors; Receptors, Oxytocin - metabolism; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure-Activity Relationship; Fissipedia; Carnivora; Indan derivatives; Sulfonamide; Rat; Nitrogen heterocycle; Rodentia; Oral administration; In vitro; Biological activity; Spiran; In vivo; Vertebrata; Mammalia; Six membered ring; Piperidine derivatives; Bicyclic compound; Carboxamide; Antagonist; Dog; Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00077a002

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.