Small molecule ligands for oxytocin and vasopressin receptors

Freidinger, Roger; Pettibone, Douglas J.

doi:10.1002/(sici)1098-1128(199701)17:1<1::aid-med1>3.0.co;2-5

Cited by 47 publications

(24 citation statements)

References 84 publications

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“…In women, L-368,899 also blocked OT-stimulated uterine activity postpartum with a potency similar to that observed in the pregnant rhesus monkey [68]. However, no further clinical evaluation was undertaken because of suboptimal oral bioavailability and pharmacokinetics [69]. L-368,899 is also brain penetrant, and experiments in one adult female monkey demonstrated that it altered maternal and sexual behavior [4].…”

Section: Oxytocin Antagonists As Tocolytic Agentsmentioning

confidence: 98%

The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents

Vrachnis

Malamas

Sifakis

et al. 2011

International Journal of Endocrinology

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Oxytocin, a hormone involved in numerous physiologic processes, plays a central role in the mechanisms of parturition and lactation. It acts through its receptor, which belongs to the G-protein-coupled receptor superfamily, while Gq/phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3) is the main pathway via which it exerts its action in the myometrium. Changes in receptor levels, receptor desensitization, and locally produced oxytocin are factors that influence the effect of oxytocin on uterine contractility in labor. Activation of oxytocin receptor causes myometrial contractions by increasing intracellular Ca+2 and production of prostaglandins. Since oxytocin induces contractions, the inhibition of its action has been a target in the management of preterm labor. Atosiban is today the only oxytocin receptor antagonist that is available as a tocolytic. However, the quest for oxytocin receptor antagonists with a better pharmacological profile has led to the synthesis of peptide and nonpeptide molecules such as barusiban, retosiban, L-368,899, and SSR-126768A. Many of these oxytocin receptor antagonists are used only as pharmacological tools, while others have tocolytic action. In this paper, we summarize the action of oxytocin and its receptor and we present an overview of the clinical and experimental data of oxytocin antagonists and their tocolytic action.

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Section: Oxytocin Antagonists As Tocolytic Agentsmentioning

confidence: 98%

The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents

Vrachnis

Malamas

Sifakis

et al. 2011

International Journal of Endocrinology

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“…L-368,899 also blocked OTstimulated uterine activity in postpartum women with a potency similar to that in the pregnant rhesus monkey (Pettibone et al, 1995). The pharmacokinetics and oral bioavailability, however, were suboptimal, and further clinical evaluation was not undertaken (Freidinger and Pettibone, 1997). L-368,899 is moreover brain penetrant.…”

Section: Oxytocinmentioning

confidence: 99%

Oxytocin and Myometrial Contractility in Labor

Vrachnis¹,

Malamas²,

Sifakis³

et al. 2012

From Preconception to Postpartum

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“…2) with distinct biological functions [3]. Its primary role involves regulation of the renal and cardiovascular functions [4].…”

Section: Arginine Vasopressin Receptors and Their Non-peptide Inhibitorsmentioning

confidence: 99%

Chemical development of the vasopressin receptor 2 antagonist SR-121463

Hermecz¹,

Sánta-Csutor

Gönczi

et al. 2001

Pure and Applied Chemistry

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A facile convergent total synthesis of the selective, potent, and orally active V 2 nonpeptide antagonist, SR-121463, was developed by modification of the discovery route. One of the late intermediates, the sulfonyl chloride 1, was synthesized from 3-hydroxybenzoic acid (19) by regioselective sulfonation, O-methylation and amidation in four steps. Another late intermediate, indolin-2-one 2, was prepared from p-phenetidine (8) through the indolin-2-one 16, where the cyclohexanone moiety of 27 was introduced into the active 3-methylene group of 16 by sequential transformation using methyl acrylate and KOtBu. After formation of the cyclic ketal moiety of 13, its ring-opening was achieved by using NaBH 4 in the presence of CCl 3 COOH. The morpholino group in 2 was introduced in accordance with the discovery approach, starting from the 2-hydroxyethoxy derivative 14 through the tosyloxy derivative 15 with morpholine in a one-pot reaction. In this way, the indolin-2-one 2 was synthesized from 8 in six steps. Finally, acylation of the indolin-2-one 2 was achieved with the sulfonyl chloride 1 in the presence of KOtBu in dimethyl sulfoxide (DMSO) at room temperature. This synthetic route proved to be applicable for the large-scale synthesis of SR-121463.

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Small molecule ligands for oxytocin and vasopressin receptors

Cited by 47 publications

References 84 publications

The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents

The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents

Oxytocin and Myometrial Contractility in Labor

Chemical development of the vasopressin receptor 2 antagonist SR-121463

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