262298-03-3Relevant articles and documents
6,7-Dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidines and their derivatives as novel corticotropin-releasing factor 1 receptor antagonists
Saito, Tetsuji,Obitsu, Tetsuo,Kondo, Takashi,Matsui, Toshiaki,Nagao, Yuuki,Kusumi, Kensuke,Matsumura, Naoya,Ueno, Sonoko,Kishi, Akihiro,Katsumata, Seishi,Kagamiishi, Yoshifumi,Nakai, Hisao,Toda, Masaaki
, p. 5432 - 5445 (2011/10/19)
To identify an orally active corticotropin-releasing factor 1 receptor antagonist, a series of 6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidines and their derivatives were designed, synthesized and evaluated. An in vitro study followed by in vivo and pharmacokinetic studies of these heterotricyclic compounds led us to the discovery of an orally active CRF1 receptor antagonist. The results of a structure-activity relationship study are presented.
PYRAZOLO [1,5-ALPHA] PYRIMIDINYL DERIVATIVES USEFUL AS CORTICOTROPIN-RELEASING FACTOR (CRF) RECEPTOR ANTAGONISTS
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Page/Page column 45, (2008/06/13)
CRF receptor antagonists are disclosed which may have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in mammals. The CRF receptor antagonists of this invention have the following structure: (I); and pharmaceutically acceptable salts, esters, solvates, stereoisomers and prodrugs thereof, wherein R1, R2a, R2b, Y, Het, n, o, R6, Ar and R7 are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same.
The discovery of 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4- methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine: A corticotropin-releasing factor (hCRF1) antagonist
Gilligan, Paul J.,Baldauf, Caryn,Cocuzza, Anthony,Chidester, Dennis,Zaczek, Robert,Fitzgerald, Lawrence W.,McElroy, John,Smith, Mark A.,Shen,Saye, Jo Anne,Christ, David,Trainor, George,Robertson, David W.,Hartig, Paul
, p. 181 - 189 (2007/10/03)
Structure-activity relationship studies led to the discovery of 4-(3- pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]- pyrimidine 11-31 (DMP904), whose pharmacological profile strongly supports the hypothesis that hCRF1 antagonists may be potent anxiolytic drugs. Compound 11-31 (hCRF1 K(i) = 1.0 ± 0.2 nM (n = 8)) was a potent antagonist of hCRF1-coupled adenylate cyclase activity in HEK293 cells (IC50 = 10.0 ± 0.01 nM versus 10 nM r/hCRF, n = 8); α-helical CRF(9-41) had weaker potency (IC50 = 286 ± 63 nM, n = 3). Analogue 11-31 had good oral activity in the rat situational anxiety test; the minimum effective dose for 11-31 was 0.3 mg/kg (po). Maximal efficacy (approximately 57% reduction in latency time in the dark compartment) was observed at this dose. Chlordiazepoxide caused a 72% reduction in latency at 20 mg/kg (po). The literature compound 1 (CP154526-1, 30 mg/kg (po)) was inactive in this test. Compound 11-31 did not inhibit open-field locomotor activity at 10, 30, and 100 mg/kg (po) in rats. In beagle dogs, this compound (5 mg/kg, iv, po) afforded good plasma levels. The key iv pharmacokinetic parameters were t(1/2), CL and V(d,ss) values equal to 46.4 ± 7.6 h, 0.49 ± 0.08 L/kg/h and 23.0 ± 4.2 L/kg, respectively. After oral dosing, the mean C(max), T(max), t(1/2) and bioavailability values were equal to 1260 ± 290 nM, 0.75 ± 0.25 h, 45.1 ± 10.2 h and 33.1%, respectively. The overall rat behavioral profile of this compound suggests that it may be an anxiolytic drug with a low motor side effect liability. (C) 2000 Elsevier Science Ltd.
