In Vitro and in Vivo Pharmacological Characterization of Ethyl-4-{trans-4-[((2S)-2-hydroxy-3-{4-hydroxy-3[(methylsulfonyl)amino]-phenoxy}propyl) Amino]cyclohexyl}benzoate Hydrochloride (SAR150640), a New Potent and Selective Human β₃-Adrenoceptor Agonist for the Treatment of Preterm Labor

Abstract

Ethyl-4-{trans-4-[((2S)-2-hydroxy-3-{4-hydroxy-3[(methylsulfonyl)amino] phenoxy}propyl) amino]cyclohexyl}benzoate hydrochloride (SAR150640) was characterized as a new potent and selective ␤ 3 -adrenoceptor agonist for the treatment of preterm labor. SAR150640 and its major metabolite, the corresponding acid 4-{trans-4-[((2S)-2-hydroxy-3-{4-hydroxy-3[(methylsulfonyl) amino] phenoxy}propyl)amino]cyclohexyl}benzoic acid (SSR500400), showed high affinity for ␤ 3 -adrenoceptors (K i ϭ 73 and 358 nM) and greater potency than (Ϫ)-isoproterenol in increasing cAMP production in membrane preparations from human neuroblastoma cells (SKNMC), which express native ␤ 3 -adrenoceptors (pEC 50 ϭ 6.5, 6.2, and 5.1, respectively). SAR150640 and SSR500400 also increased cAMP production in membrane preparations from human uterine smooth muscle cells (UtSMC), which also express native ␤ 3 -adrenoceptors (pEC 50 ϭ 7.7 and 7.7, respectively). In these cells, SAR150640 dose-dependently inhibited oxytocin-induced intracellular Ca 2ϩ mobilization and extracellular signal-regulated kinase 1/2 phosphorylation. SAR150640 and SSR500400 had no ␤ 1 -or ␤ 2 -agonist or antagonist activity in guinea pig atrium and trachea, or in human isolated atrium and bronchus preparations. Both compounds concentration-dependently inhibited spontaneous contractions in human near-term myometrial strips, with greater potency than salbutamol and 4-[3-[(1,1-dimethylethyl)-amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP12177) (pIC 50 ϭ 6.4, 6.8, 5.9, and 5.8, respectively), but with similar potency to (Ϫ)-isoproterenol and atosiban (oxytocin/vasopressin V 1 a receptor antagonist). SAR150640 also inhibited the contractions induced by oxytocin and prostaglandin F 2␣ . In vivo, after intravenous administration, SAR150640 (1and 6 mg/kg), but not atosiban (6 mg/kg), dosedependently inhibited myometrial contractions in conscious unrestrained female cynomolgus monkeys, with no significant effects on heart rate or blood pressure. In contrast, salbutamol (50 and 250 g/kg) had no inhibitory effect on uterine contractions, but it dose-dependently increased heart rate. These findings indicate a potential for the therapeutic use of SAR150640 in mammals during preterm labor.Premature labor and its consequence, preterm delivery, defined by the World Health Organization as gestational age at birth of less than 37 complete gestational weeks, are major Article, publication date, and citation information can be found at

ADRB3 Adrenergic Receptor Is a Key Regulator of Human Myometrial Apoptosis and Inflammation During Chorioamnionitis1

“…In a third set of experiments aimed at assessing the ability of ADRB3 stimulation to oppose LPS-induced apoptosis, myometrial strips were incubated with LPS (10 lg/ml) for 48 h in the presence or absence of SAR150640, a selective ADRB3 agonist [30] (0.1 lM, 1 lM, and 10 lM), added immediately prior to begin LPS stimulation. Time-matched control experiments were performed with the solvent of SAR150640; that is, distilled water containing ethanol 0.3% and DMSO 0.02% as final bath concentration, both nonstimulated and LPS-stimulated myometrial samples.…”

“…It has been described that lipopolysaccharide (LPS) produces a large decrease in adipose tissue ADRB3 transcription and function [29]; nevertheless, there are no published data demonstrating an anti-inflammatory effect for ADRB3 stimulation. Since we have suggested its potential interest in the pharmacologic management of preterm labor, the aims of this study were: 1) to study the cellular consequences of chorioamnionitis in human myometrium; 2) to develop an in vitro model of chorioamnionitis induced by Escherichia coli LPS in human myometrium in order to analyze the myometrial consequences of chorioamnionitis and to assess the ability of the newly described selective ADRB3 agonist, SAR150640 (ethyl-4-(trans-4-[((2S)-2-hydroxy-3-(4-hydroxy-3[(methylsulfonyl)amino]phenoxy)propyl)amino]cyclohexyl)benzoate hydrochloride) [30] to oppose this LPS-induced chorioamnionitis.…”

Effects and Selectivity of CL 316243, Beta-3-Adrenoceptor Agonist, in Term-Pregnant Rat Myometrium

“…It has been reported the existence of functional β 3 -adrenoceptors in the human myometrium [7,8], where the β 3 -adrenoceptor is predominant over the β 2 -adrenoceptor, and, moreover, β 3 -adrenoceptor expression increases at the end of pregnancy [9,10]. Although the potential cardiovascular effects of β 3 -adrenoreceptor agonists are complex, there is in vitro evidence that their potency is less in vascular tissue than that of β 2 -adrenoreceptor agonists [11].…”

Upregulation of β₃-Adrenergic Receptor mRNA in Human Colon Cancer: A Preliminary Study

“…11–14]. β 3 -AR is expressed in several tissues (table 1), such as adipose tissue [7], heart [8], uterus [9], bladder [10] and colon [11], and modulates different physiological functions. Due to its wide tissue distribution, it can be considered a reasonable drug target for the treatment of several pathologies [12].…”