4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine Hydrochloride (SSR125543A): A Potent and Selective Corticotrophin-Releasing Factor1Receptor Antagonist. I. Biochemical and Pharmacological Characterization
| Autor: | Régis Steinberg, Jean-Pierre Maffrand, Pierre Roger, Georgette Gout, Philippe Soubrie, Evelyne Fontaine, Christine Lair, Danielle Gully, Marc Pascal, Valerie Darre, Michel Geslin, Jacques Simiand, Gérard Le Fur, Rebecca M. Pruss, Pierre-Eric Rouby, Bernard Scatton, Laurence Serva, Josette Guitard, Claudine Marcy, D. Rodier, Guy Griebel |
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| Rok vydání: | 2002 |
| Předmět: |
Pharmacology
Agonist endocrine system medicine.medical_specialty medicine.drug_class Hydrochloride Stimulation Receptor antagonist chemistry.chemical_compound Endocrinology chemistry Internal medicine medicine Molecular Medicine Receptor hormones hormone substitutes and hormone antagonists Ex vivo Acetylcholine Hormone medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 301:322-332 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 4-(2-Chloro-4-methoxy-5-methylphenyl)- N -[(1 S )-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]5-methyl- N -(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A), a new 2-aminothiazole derivative, shows nanomolar affinity for human cloned or native corticotrophin-releasing factor (CRF) 1 receptors (p K i values of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF 1 versus CRF 2α receptor and CRF binding protein. SSR125543A antagonizes CRF-induced stimulation of cAMP synthesis in human retinoblastoma Y 79 cells (IC 50 = 3.0 ± 0.4 nM) and adrenocorticotropin hormone (ACTH) secretion in mouse pituitary tumor AtT-20 cells. SSR125543A is devoid of agonist activity in these models. Its brain penetration was demonstrated in rats by using an ex vivo [ 125 I-Tyr 0 ] ovine CRF binding assay. SSR125543A displaced radioligand binding to the CRF 1 receptor in the brain with an ID 50 of 6.5 mg/kg p.o. (duration of action >24 h). SSR125543A also inhibited the increase in plasma ACTH levels elicited in rats by i.v. CRF (4 μg/kg) injection (ID 50 = 1, 5, or 5 mg/kg i.v., i.p., and p.o., respectively); this effect lasted for more than 6 h when the drug was given orally at a dose of 30 mg/kg. SSR125543A (10 mg/kg p.o.) reduced by 73% the increase in plasma ACTH levels elicited by a 15-min restraint stress in rats. Moreover, SSR125543A (20 mg/kg i.p.) also antagonized the increase of hippocampal acetylcholine release induced by i.c.v. injection of 1 μg of CRF in rats. Finally, SSR125543A reduced forepaw treading induced by i.c.v. injection of 1 μg of CRF in gerbils (ID 50 = ∼10 mg/kg p.o.). Altogether, these data indicate that SSR125543A is a potent, selective, and orally active CRF 1 receptor antagonist. |
| Databáze: | OpenAIRE |
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