title: Pharmacology of (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino) -1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide, a new potent and selective nonpeptide antagonist of the oxytocin receptor.
abstract: We have discovered a new, potent, selective, and orally active oxytocin receptor antagonist, (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (compound 1). We report the biochemical, pharmacological, and pharmacokinetic characterization in vitro and in vivo of this compound. Compound 1 competitively inhibits binding of [3H]oxytocin and the peptide antagonist 125I-ornithine vasotocin analog to human and rat oxytocin receptor expressed in human embryonic kidney 293-EBNA or Chinese hamster ovary cells with nanomolar potency. Selectivity against vasopressin receptor subtypes is >6-fold for V1a and >350-fold for V2 and V1b. Compound 1 inhibits oxytocin-evoked intracellular Ca2+ mobilization (IC50 = 8 nM). Compound 1 has no intrinsic agonist activity at the oxytocin receptor. Oxytocininduced contraction of isolated rat uterine strips is blocked by compound 1 (pA2 = 7.82). In anesthetized nonpregnant rats, single administration of compound 1 by i.v. or oral routes causes dose-dependent inhibition of contractions elicited by repeated injections of oxytocin with ED50 = 3.5 mg/kg i.v. and 89 mg/kg p.o., respectively. Compound 1 significantly inhibits spontaneous uterine contractions in pregnant rats near term when administered intravenously or orally. We conclude that compound 1 is a potent, selective, and orally active nonpeptide oxytocin receptor antagonist, which is a suitable candidate for evaluation as a potential tocolytic agent for the management of preterm labor.
authors.affiliation: Istituto di Ricerche Biomediche "A Marxer", LCG Bioscience, Colleretto Giacosa, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Cirillo
authors.forename: Enrico
authors.initials: E
authors.lastname: Gillio Tos
authors.forename: Matthias K
authors.initials: MK
authors.lastname: Schwarz
authors.forename: Anna
authors.initials: A
authors.lastname: Quattropani
authors.forename: Alexander
authors.initials: A
authors.lastname: Scheer
authors.forename: Marc
authors.initials: M
authors.lastname: Missotten
authors.forename: Jerome
authors.initials: J
authors.lastname: Dorbais
authors.forename: Anthony
authors.initials: A
authors.lastname: Nichols
authors.forename: Francesco
authors.initials: F
authors.lastname: Borrelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Giachetti
authors.forename: Lucia
authors.initials: L
authors.lastname: Golzio
authors.forename: Paolo
authors.initials: P
authors.lastname: Marinelli
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Thomas
authors.forename: Claude
authors.initials: C
authors.lastname: Chevillard
authors.forename: Florence
authors.initials: F
authors.lastname: Laurent
authors.forename: Karine
authors.initials: K
authors.lastname: Portet
authors.forename: Claude
authors.initials: C
authors.lastname: Barberis
authors.forename: Andre
authors.initials: A
authors.lastname: Chollet
mesh_terms: D000758:Anesthesia; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D015237:Dinoprost / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007097:Imines / Q000494:pharmacology*; D010121:Oxytocin / Q000494:pharmacology; D011247:Pregnancy; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors*; D017483:Receptors, Vasopressin / Q000378:metabolism; D014590:Uterine Contraction / Q000187:drug effects*
chemical_list: D007097:Imines; C475770:N-(2-hydroxy-2-phenylethyl)-4-(methoxyimino)-1-((2'-methyl(1,1'-biphenyl)-4-yl)carbonyl)-2-pyrrolidinecarboxamide; D011759:Pyrrolidines; D018045:Receptors, Oxytocin; D017483:Receptors, Vasopressin; D010121:Oxytocin; D015237:Dinoprost