Nanomolar-affinity, non-peptide oxytocin receptor antagonists

B E Evans; G F Lundell; K F Gilbert; M G Bock; K E Rittle; L A Carroll; P D Williams; J M Pawluczyk; J L Leighton; M B Young

doi:10.1021/jm00077a002

Nanomolar-affinity, non-peptide oxytocin receptor antagonists

J Med Chem. 1993 Dec 10;36(25):3993-4005. doi: 10.1021/jm00077a002.

Authors

B E Evans¹, G F Lundell, K F Gilbert, M G Bock, K E Rittle, L A Carroll, P D Williams, J M Pawluczyk, J L Leighton, M B Young, et al.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.

PMID: 8258821
DOI: 10.1021/jm00077a002

Abstract

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.

MeSH terms

Animals
Binding Sites / drug effects
Female
Oxytocin / antagonists & inhibitors
Piperazines / chemical synthesis*
Piperazines / chemistry
Piperazines / pharmacology
Piperidines / chemistry
Piperidines / pharmacology*
Rats
Receptors, Oxytocin / antagonists & inhibitors*
Receptors, Oxytocin / metabolism
Spiro Compounds / chemical synthesis*
Spiro Compounds / chemistry
Spiro Compounds / pharmacology*
Structure-Activity Relationship

Substances

Piperazines
Piperidines
Receptors, Oxytocin
Spiro Compounds
L 366509
Oxytocin