3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine: a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism.
We describe a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) inhibited 125I-sauvagine binding to rat pituitary membranes and cloned human CRF1 with subnanomolar affinities, with no detectable activity at the CRF2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125I-sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of approximately 1.3 mg/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine) and CP154526 (N-butyl-N-ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (1-10 mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.
Gehlert
Donald R
DR
Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Cippitelli
Andrea
A
Thorsell
Annika
A
Lê
Anh Dzung
AD
Hipskind
Philip A
PA
Hamdouchi
Chafiq
C
Lu
Jianliang
J
Hembre
Erik J
EJ
Cramer
Jeffrey
J
Song
Min
M
McKinzie
David
D
Morin
Michelle
M
Ciccocioppo
Roberto
R
Heilig
Markus
M
D000284:Administration, Oral; D000428:Alcohol Drinking / Q000523:psychology; D000437:Alcoholism / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology; D029845:Amphibian Proteins; D000818:Animals; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage; D008297:Male; D036361:Peptide Hormones; D010455:Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011724:Pyridazines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012646:Self Administration; D013312:Stress, Physiological / Q000523:psychology; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000099052:CRF Receptor, Type 1
C518650:3-(4-chloro-2-morpholin-4-ylthiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethylimidazo(1,2-b)pyridazine; D029845:Amphibian Proteins; D036361:Peptide Hormones; D010455:Peptides; D011724:Pyridazines; D018019:Receptors, Corticotropin-Releasing Hormone; D013844:Thiazoles; D000431:Ethanol; D000099052:CRF Receptor, Type 1; C025727:sauvagine