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.
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/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 microg of CRF in rats. Finally, SSR125543A reduced forepaw treading induced by i.c.v. injection of 1 microg of CRF in gerbils (ID(50) = approximately 10 mg/kg p.o.). Altogether, these data indicate that SSR125543A is a potent, selective, and orally active CRF(1) receptor antagonist.
Gully
Danielle
D
Exploratory Research Department, Sanofi-Synthelabo, Toulouse, France. danielle.gully@sanofi-synthelabo.com
Geslin
Michel
M
Serva
Laurence
L
Fontaine
Evelyne
E
Roger
Pierre
P
Lair
Christine
C
Darre
Valerie
V
Marcy
Claudine
C
Rouby
Pierre-Eric
PE
Simiand
Jacques
J
Guitard
Josette
J
Gout
Georgette
G
Steinberg
Regis
R
Rodier
Daniel
D
Griebel
Guy
G
Soubrie
Philippe
P
Pascal
Marc
M
Pruss
Rebecca
R
Scatton
Bernard
B
Maffrand
Jean-Pierre
JP
Le Fur
Gerard
G
D000109:Acetylcholine / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D005260:Female; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D017551:Microdialysis; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D000099052:CRF Receptor, Type 1
C451725:4-(2-chloro-4-methoxy-5-methylphenyl)-N(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine; C101531:CRF receptor type 2; D018019:Receptors, Corticotropin-Releasing Hormone; D013844:Thiazoles; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D000109:Acetylcholine