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

Abstract

L-368,899 [1S-((-7,7-dimethyl-2-endo-(2S-amino-4-(methylsulfonyl)bu~ramido)-bicyclo(2.2.1)-heptan-l-yl)methanesulfonyl)-4-(2-methylphenyl)piper~inel 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)-VI 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 Fg/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 pg/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. o 1993 WiIey-Liss, inc.

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

“…In the past, other groups have identified nonpeptide OT-R antagonists with very interesting in vitro and in vivo profiles (Clineschmidt et al, 1991;Pettibone et al 1993;Williams et al, 1998), but no reports are available on the current stage of the development of these compounds. The need to identify new selective and nonpeptide oxytocin receptor antagonist therefore remains.…”

Neurochemistry of the paraventricular nucleus of the hypothalamus: Implications for cardiovascular regulation

“…This antagonist has been shown to have comparable potency for the V1a receptor and thus is able to block both oxytocin-mediated and V1a receptor mediated responses (Yang et al, 2002). Furthermore, the non-peptide oxytocin receptor antagonist L-368,899, has been shown to be selective for the oxytocin receptor over the V1a receptor (Pettibone et al, 1993). In addition, RSNA can be inhibited by oxytocin and is an effect mediated by oxytocin receptors since both antagonists blocked the action of oxytocin and neither a V1a antagonist or kynurenic acid does not prevent it.…”

The Role of Drug Metabolism in Drug Discovery: A Case Study in the Selection of an Oxytocin Receptor Antagonist for Development

“…These nonpeptidyl antagonists are represented by lead structures containing spiroindenylpiperidinecamphor-sulfonamide moieties (3,6,14). Further modification of these structures with potencyenhancing groups led to a group of potent, selective antagonists represented by Compounds I (L-368,899), II, and III ( Fig.…”

“…Further modification of these structures with potencyenhancing groups led to a group of potent, selective antagonists represented by Compounds I (L-368,899), II, and III ( Fig. 1) ( 13,19). As (14,19).…”