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 (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 >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.
Footnotes
- Abbreviations:
- CRF
- corticotropin-releasing factor
- ACTH
- adrenocorticotropin hormone
- HPA
- hypothalomo-pituitary-adrenal axis
- CRF-BP
- corticotropin-releasing factor-binding protein
- DMSO
- dimethyl sulfoxide
- CHO
- Chinese hamster ovary
- PBS
- phosphate-buffered saline
- ANOVA
- analysis of variance
- ACh
- acetylcholine
- R-121919
- 3-[6-(dimethylamino)-4-methyl-pyrid-3-yl]-2,5-dimethyl-N,N-dipropyl-pyrazolo[2,3-a]pyrimidin-7-amine
- antalarmin
- butylethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine
- Received October 11, 2001.
- Accepted December 31, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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