PMID: 11907190Mar 22, 2002Paper

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 factor(1) receptor antagonist. I. Biochemical and pharmacological characterization

The Journal of Pharmacology and Experimental Therapeutics
Danielle GullyG Le Fur

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(i) values of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF(1) versus CRF(2 alpha) 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 microg/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...Continue Reading

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Citations

Feb 6, 2004·European Journal of Pharmacology·Shigeyuki ChakiThomas Steckler
Mar 10, 2004·Pharmacology, Biochemistry, and Behavior·Catherine FarrokhiRobert J Blanchard
Nov 11, 2003·Trends in Pharmacological Sciences·Andrew HolmesGuy Griebel
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Jul 11, 2003·Bioorganic & Medicinal Chemistry Letters·Kevin J HodgettsDarío Doller
Oct 21, 2011·Nature Reviews. Neuroscience·Markus HeiligCharles P O'Brien
Feb 3, 2006·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Caroline LouisGuy Griebel
Mar 15, 2011·Expert Opinion on Investigational Drugs·Marcelo Paez-PeredaFlorian Holsboer
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Jul 17, 2007·Trends in Neurosciences·Markus Heilig, George F Koob
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Jan 8, 2005·American Journal of Physiology. Gastrointestinal and Liver Physiology·Christophe PorcherBruno Bonaz
Feb 13, 2014·British Journal of Pharmacology·Stephen P H AlexanderUNKNOWN CGTP Collaborators
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Apr 1, 2011·British Journal of Pharmacology·Simeon J RamseyPiet H van der Graaf

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