Abstract

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 (pK_ivalues of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF₁ versus CRF_2α 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.