Croci Tiziano, Cecchi Roberto, Marini Pietro, Rouget Céline, Viviani Nunzia, Germain Guy, Guagnini Fabio, Fradin Yvon, Descamps Laurence, Pascal Marc, Advenier Charles, Breuiller-Fouché Michelle, Leroy Marie-Josèphe, Bardou Marc
Exploratory Research Department, Sanofi-Midy Research Center, sanofi-aventis, SpA., Via G. B. Piranesi, 38, 20137 Milan, Italy.
J Pharmacol Exp Ther. 2007 Jun;321(3):1118-26. doi: 10.1124/jpet.106.119123. Epub 2007 Mar 9.
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 beta(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 beta(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 beta(3)-adrenoceptors (pEC(50) = 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 beta(3)-adrenoceptors (pEC(50) = 7.7 and 7.7, respectively). In these cells, SAR150640 dose-dependently inhibited oxytocin-induced intracellular Ca(2+) mobilization and extracellular signal-regulated kinase 1/2 phosphorylation. SAR150640 and SSR500400 had no beta(1)- or beta(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) = 6.4, 6.8, 5.9, and 5.8, respectively), but with similar potency to (-)-isoproterenol and atosiban (oxytocin/vasopressin V(1)a receptor antagonist). SAR150640 also inhibited the contractions induced by oxytocin and prostaglandin F(2alpha). 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 microg/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.
4-[反式-4-[((2S)-2-羟基-3-[4-羟基-3-[(甲基磺酰基)氨基]苯氧基]丙基)氨基]环己基]苯甲酸乙酯盐酸盐（SAR150640）被鉴定为一种新型强效且选择性的β(3)-肾上腺素能受体激动剂，用于治疗早产。SAR150640及其主要代谢产物，相应的酸4-[反式-4-[((2S)-2-羟基-3-[4-羟基-3-[(甲基磺酰基)氨基]苯氧基]丙基)氨基]环己基]苯甲酸（SSR500400），对β(3)-肾上腺素能受体显示出高亲和力（K(i)分别为73和358 nM），并且在增加来自表达天然β(3)-肾上腺素能受体的人神经母细胞瘤细胞（SKNMC）的膜制剂中的环磷酸腺苷（cAMP）生成方面比(-)-异丙肾上腺素具有更高的效力（pEC(50)分别为6.5、6.2和5.1）。SAR150640和SSR500400还增加了来自人子宫平滑肌细胞（UtSMC）的膜制剂中的cAMP生成，该细胞也表达天然β(3)-肾上腺素能受体（pEC(50)分别为7.7和7.7）。在这些细胞中，SAR150640剂量依赖性地抑制催产素诱导的细胞内Ca(2+)动员和细胞外信号调节激酶1/2磷酸化。SAR150640和SSR500400在豚鼠心房和气管或人离体心房和支气管制剂中没有β(1)-或β(2)-激动剂或拮抗剂活性。两种化合物均浓度依赖性地抑制人足月子宫肌条的自发收缩，效力大于沙丁胺醇和4-[3-[(1,1-二甲基乙基)-氨基]-2-羟基丙氧基]-1,3-二氢-2H-苯并咪唑-2-酮盐酸盐（CGP12177）（pIC(50)分别为6.4、6.8、5.9和5.8），但与(-)-异丙肾上腺素和阿托西班（催产素/血管加压素V(1)a受体拮抗剂）效力相似。SAR150640还抑制催产素和前列腺素F(2α)诱导的收缩。在体内，静脉给药后，SAR150640（1和6 mg/kg），而不是阿托西班（6 mg/kg），剂量依赖性地抑制清醒不受约束的雌性食蟹猴的子宫肌收缩，对心率或血压无显著影响。相比之下，沙丁胺醇（50和250 μg/kg）对子宫收缩无抑制作用，但它剂量依赖性地增加心率。这些发现表明SAR150640在哺乳动物早产期间具有治疗应用潜力。
