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.
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.
Cirillo
Rocco
R
Istituto di Ricerche Biomediche "A Marxer", LCG Bioscience, Colleretto Giacosa, Italy.
Gillio Tos
Enrico
E
Schwarz
Matthias K
MK
Quattropani
Anna
A
Scheer
Alexander
A
Missotten
Marc
M
Dorbais
Jerome
J
Nichols
Anthony
A
Borrelli
Francesco
F
Giachetti
Claudio
C
Golzio
Lucia
L
Marinelli
Paolo
P
Thomas
Russell J
RJ
Chevillard
Claude
C
Laurent
Florence
F
Portet
Karine
K
Barberis
Claude
C
Chollet
Andre
A
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*
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