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CELLULAR AND MOLECULAR

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 ₃-Adrenoceptor Agonist for the Treatment of Preterm Labor

Exploratory Research Department, Sanofi-Midy Research Center, sanofi-aventis S.p.A., Milan, Italy (T.C., R.C., P.M., C.R., N.V., F.G.); Exploratory Research Department, sanofi-aventis Recherche & Development, Toulouse, France (M.P.); Drug Safety Evaluation, Vitry Sur Sein, Paris, France (Y.F.); DMPK, Montpellier, France (L.D.); Laboratoire de Physiopathologie et Pharmacologie Cardiovasculaires, Facultéde Médecine, Dijon, France (M.B.); Institut National de la Recherche Agronomique, Biologie du Développement et Reproduction, Centre de Recherches de Jouy, Jouy-en-Josas, France (G.G.); Institut National de la Santé et de la Recherche Médicale, Unité 767, Paris, France (M.B.-F., M.-J.L.); and Département de Pharmacologie, UPRES EA220, UFR des Saints Pères, Paris, France (C.A.)

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 = 73 and 358 nM) and greater potency than (-)-isoproterenol in increasing cAMP production in membrane preparations from human neuroblastoma cells (SKNMC), which express native ₃-adrenoceptors (pEC₅₀ = 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 (pEC₅₀ = 7.7 and 7.7, respectively). In these cells, SAR150640 dose-dependently inhibited oxytocin-induced intracellular Ca²⁺ 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) (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 prostaglandin F₂. In vivo, after intravenous administration, SAR150640 (1 and 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 it dose-dependently increased heart rate. These findings indicate a potential for the therapeutic use of SAR150640 in mammals during preterm labor.

Address correspondence to: Dr. Tiziano Croci, Sanofi-Midy Research Center, sanofi-aventis, S.p.A., Via G. B. Piranesi, 38, 20137 Milan, Italy. E-mail: tiziano.croci{at}sanofi-aventis.com

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