Cited by 43Neuroendocrine regulation and behaviorPreterm Birth and ChorioamnionitisNeuropeptides and Animal Physiology

L-368,899, a potent orally active oxytocin antagonist for potential use in preterm labor

Pettibone, D. J., Clineschmidt, B. V., Guidotti, M. T., Lis, E. V., Reiss, D. R., Woyden, C. J., Bock, M. G., Evans, B. E. +13 more·1993·Drug Development Research

Abstract

Abstract L‐368,899 [1S‐(‐7,7‐dimethyl‐2‐endo‐(2S‐amino‐4‐(methylsulfonyl)butyramido)‐bicyclo(2.2.1)‐heptan‐1‐yl)methanesulfonyl)‐4‐(2‐methylphenyl)piperazine] was characterized in vitro and in vivo as a potent and selective, orally bioavailable oxytocin (OT) antagonist. L‐368,899 exhibits high affinity for rat (Ki, 3.6 nM) and human (Ki, 13 nM) uterine OT receptors with selectivity versus liver arginine‐vasopressin (AVP)‐V1 and kidney AVP‐V2 receptors in both species. In vitro, L‐368,899 is a potent and competitive OT antagonist in the rat isolated uterus (pA2, 8.9) and mouse anococcygeus muscle (pA2, 8.3) and is inactive against a number of different contractile agents in these preparations. L‐368,899 also inhibits OT‐stimulated phosphatidylinositol turnover in rat uterine slices and exhibits no agonist‐like activity in any of the in vitro assays. In vivo, L‐368,899 selectively antagonizes the uterine contractile effects of OT in the anesthetized rat given both i.v. and intraduodenally (i.d.) (AD50; 350 μg/kg i.v., 7 mg/kg i.d.) with a moderate duration of action. In near‐term pregnant rhesus macaques, L‐368,899 is a potent inhibitor of OT‐stimulated uterine activity (AD50, 27 μg/kg i.v.) and OT‐mediated spontaneous, nocturnal uterine contractions. L‐368,899 is orally bioavailable in several species and, combined with adequate aqueous solubility, represents a potential new tocolytic agent for both oral and i.v. use. © 1993 wiley‐Liss, Inc.

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Crossref · 10.1002/ddr.430300305

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Authors
Pettibone, D. J., Clineschmidt, B. V., Guidotti, M. T., Lis, E. V., Reiss, D. R., Woyden, C. J., Bock, M. G., Evans, B. E., Freidinger, R. M., Hobbs, D. W., Veber, D. F., Williams, P. D., Chiu, S. ‐. L., Thompson, K. L., Schorn, T. W., Siegl, P. K. S., Kaufman, M. J., Cukierski, M. A., Haluska, G. J., Cook, M. J., & Novy, M. J.
Affiliations
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • Oregon National Primate Research Center (US)
Corresponding author
Pettibone, D. J.
Venue
Drug Development Research
Publisher
Wiley
Published
1993-11
Volume
30
Issue
3
Pages
129-142
ISSN
  • 0272-4391 (ISSN-L)
  • 1098-2299
OpenAlex
W1981764195
Cited by
43
References
42
Citations by year
2024: 1 · 2022: 2 · 2021: 1 · 2017: 2 · 2015: 3 · 2014: 1 · 2013: 1 · 2012: 1
FWCI
2.63
Type
journal article
Language
en
Open access
closed
Locations
Drug Development Research (publishedVersion)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Health Sciences › Medicine › Epidemiology › Preterm Birth and Chorioamnionitis
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
L-368,899, oxytocin antagonist, tocolytic agents, preterm labor, oral bioavailability, intraduodenal administration, phosphatidylinositol turnover, uterine contractility

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