459856-18-9Relevant academic research and scientific papers
The development of a robust process for a CRF1 receptor antagonist
Broxer, Sevrine,Fitzgerald, Monica A.,Sfouggatakis, Chris,Defreese, Jessica L.,Barlow, Evan,Powers, Gerald L.,Peddicord, Michael,Su, Bao-Ning,Tai-Yuen, Yue,Pathirana, Charles,Sherbine, James P.
, p. 343 - 352 (2011)
A scalable and robust process was developed for the preparation of pexacerfont (2), a pyrazolotriazine corticotropin-releasing factor receptor 1 antagonist (CRF1). The formation of the core hydroxypyrazolotriazine moiety was achieved through two consecutive cyclizations of a semicarbazide, employing reaction conditions that are significantly milder than those reported in the literature. Further conversion to the key chloropyrazolotriazine intermediate was accomplished through a novel catalytic process using phosphorous oxychloride as the chlorinating agent. The active pharmaceutical ingredient 2 was obtained in >99.5% purity with a 68% overall yield for the six synthetic steps.
Synthesis and structure-activity relationships of 8-(pyrid-3-yl)pyrazolo[1, 5-a]-1,3,5-triazines: Potent, orally bioavailable corticotropin releasing factor receptor-1 (CRF1) antagonists
Gilligan, Paul J.,Clarke, Todd,He, Liqi,Lelas, Snjezana,Li, Yu-Wen,Heman, Karen,Fitzgerald, Lawrence,Miller, Keith,Zhang, Ge,Marshall, Anne,Krause, Carol,McElroy, John F.,Ward, Kathyrn,Zeller, Kim,Wong, Harvey,Bai, Steven,Saye, Joanne,Grossman, Scott,Zaczek, Robert,Arneric, Stephen P.,Hartig, Paul,Robertson, David,Trainor, George
experimental part, p. 3084 - 3092 (2010/02/28)
This report describes the syntheses and structure-activity relationships of 8-(substituted pyridyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF1) receptor antagonists. These CRF1 receptor antagonists may be potential anxiolytic or antidepressant drugs. This research resulted in the discovery of compound 13-15, which is a potent, selective CRF1 antagonist (hCRF1 IC50 = 6.1 ± 0.6 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 13-15 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 13-15 has been advanced to clinical trials.
