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Vol. 301, Issue 1, 322-332, April 2002

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 Factor1 Receptor Antagonist. I. Biochemical and Pharmacological Characterization

Danielle Gully, Michel Geslin, Laurence Serva, Evelyne Fontaine, Pierre Roger, Christine Lair, Valerie Darre, Claudine Marcy, Pierre-Eric Rouby, Jacques Simiand, Josette Guitard, Georgette Gout , Regis Steinberg, Daniel Rodier, Guy Griebel, Philippe Soubrie, Marc Pascal, Rebecca Pruss, Bernard Scatton, Jean-Pierre Maffrand and Gerard Le Fur

Exploratory Research Department, Sanofi-Synthelabo, Toulouse, France (D.G., M.G., L.S., E.F., P.R., C.L., V.D., C.M., P.E.R., M.P.) and Strasbourg, France (R.P.); Central Nervous System Department, Sanofi-Synthelabo, Toulouse, France (J.S., J.G., G.G.), Montpellier, France (R.G., D.R., P.S.), and Paris, France (G.G.); Discovery Research Division, Sanofi-Synthelabo, Paris, France (B.S., J.P.M., G.L.F.)

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 new 2-aminothiazole derivative, shows nanomolar affinity for human cloned or native corticotrophin-releasing factor (CRF)1 receptors (pKi values of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF1 versus CRF2alpha receptor and CRF binding protein. SSR125543A antagonizes CRF-induced stimulation of cAMP synthesis in human retinoblastoma Y 79 cells (IC50 = 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 [125I-Tyr0] ovine CRF binding assay. SSR125543A displaced radioligand binding to the CRF1 receptor in the brain with an ID50 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 (ID50 = 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 (ID50 = ~10 mg/kg p.o.). Altogether, these data indicate that SSR125543A is a potent, selective, and orally active CRF1 receptor antagonist.

0022-3565/02/3011-0322$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics.