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 beta3-adrenoceptor agonist for the treatment of preterm labor.
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.
Croci
Tiziano
T
Exploratory Research Department, Sanofi-Midy Research Center, sanofi-aventis, SpA., Via G. B. Piranesi, 38, 20137 Milan, Italy. tiziano.croci@sanofi-aventis.com
Cecchi
Roberto
R
Marini
Pietro
P
Rouget
Céline
C
Viviani
Nunzia
N
Germain
Guy
G
Guagnini
Fabio
F
Fradin
Yvon
Y
Descamps
Laurence
L
Pascal
Marc
M
Advenier
Charles
C
Breuiller-Fouché
Michelle
M
Leroy
Marie-Josèphe
MJ
Bardou
Marc
M
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008252:Macaca fascicularis; D015394:Molecular Structure; D009215:Myometrium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007752:Obstetric Labor, Premature / Q000517:prevention & control*; D010121:Oxytocin / Q000494:pharmacology; D011247:Pregnancy; D011412:Propanolamines / Q000494:pharmacology; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015149:Tocolytic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection; D014590:Uterine Contraction / Q000187:drug effects; D014668:Vasotocin / Q000031:analogs & derivatives / Q000494:pharmacology
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D001565:Benzoates; D011412:Propanolamines; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides; D015149:Tocolytic Agents; C521336:ethyl 4-(4-((2-hydroxy-3-(4-hydroxy-3-((methylsulfonyl)amino)phenoxy)propyl)amino)cyclohexyl)benzoate; C047046:atosiban; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D010121:Oxytocin; D000242:Cyclic AMP; D007545:Isoproterenol; D000420:Albuterol; C033394:CGP 12177; D014668:Vasotocin