Received for publication December 27, 2006.
Revised March 7, 2007.
Accepted for publication March 7, 2007.

In vitro and in vivo pharmacological characterization of SAR150640 (ethyl-4-{trans-4-[((2S)-2-hydroxy-3-{4-hydroxy-3[(methylsulfonyl)amino]phenoxy}propyl) amino]cyclohexyl}benzoate hydrochloride), a new potent and selective human ₃-adrenoceptor agonist for the treatment of preterm labor

Abstract

SAR150640, (ethyl-4-{trans-4-[((2S)-2-hydroxy-3-{4-hydroxy-3[(methylsulfonyl)amino] phenoxy}propyl) amino]cyclohexyl}benzoate hydrochloride) 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 SSR500400, showed high affinity for ₃-adrenoceptors (Ki 73 and 358 nM), and greater potency than (-)isoproterenol in increasing cAMP production in membrane preparations from human neuroblastoma (SKNMC) cells, which express native ₃-adrenoceptors, pEC₅₀ 6.5, 6.0 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, pEC₅₀ 7.7 and 7.7 respectively. In these cells SAR150640 dose-dependently inhibited oxytocin-induced intracellular Ca²⁺ mobilization and ERK1/2 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 CGP12177 (pIC₅₀ 6.4, 6.8, 5.9 and 5.8 respectively), but with similar potency to (-)-isoproterenol and atosiban (oxytocin/vasopressin V₁a receptor antagonist). SAR150640 also inhibited the contractions induced by oxytocin and the prostaglandin PGF2. In vivo, after intravenous administration, SAR150640 (1and 6 mg/kg), but not atosiban (6 mg/kg), dose-dependently 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 µg/kg) had no inhibitory effect on uterine contractions but dose-dependently increased heart rate. These findings indicate a potential for the therapeutic utilization of SAR150640 in mammals during preterm labor.

Key words: Beta3-agonists, ERK1/2, SAR150640A, UtSMC, preterm delivery, uterus

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