RT Journal Article
SR Electronic
T1 4-(2-Chloro-4-methoxy-5-methylphenyl)-<em>N</em>-[(1<em>S</em>)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-<em>N</em>-(2-propynyl)-1,3-thiazol-2-amine Hydrochloride (SSR125543A): A Potent and Selective Corticotrophin-Releasing Factor<sub>1</sub> Receptor Antagonist. I. Biochemical and Pharmacological Characterization
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 322
OP 332
DO 10.1124/jpet.301.1.322
VO 301
IS 1
A1 Danielle Gully
A1 Michel Geslin
A1 Laurence Serva
A1 Evelyne Fontaine
A1 Pierre Roger
A1 Christine Lair
A1 Valerie Darre
A1 Claudine Marcy
A1 Pierre-Eric Rouby
A1 Jacques Simiand
A1 Josette Guitard
A1 Georgette Gout
A1 Regis Steinberg
A1 Daniel Rodier
A1 Guy Griebel
A1 Philippe Soubrie
A1 Marc Pascal
A1 Rebecca Pruss
A1 Bernard Scatton
A1 Jean-Pierre Maffrand
A1 Gerard Le Fur
YR 2002
UL http://jpet.aspetjournals.org/content/301/1/322.abstract
AB 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 (pKivalues of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF1 versus CRF2α 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 &gt;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. The American Society for Pharmacology and Experimental Therapeutics