Q1 · MEDICINE
Article
Author: Grossman, Scott ; Ward, Kathyrn ; Arneric, Stephen P. ; Saye, Joanne ; Hartig, Paul ; Zeller, Kim ; Clarke, Todd ; Gilligan, Paul J. ; Zhang, Ge ; Wong, Harvey ; Lelas, Snjezana ; Robertson, David ; Heman, Karen ; McElroy, John F. ; Zaczek, Robert ; He, Liqi ; Bai, Steven ; Trainor, George ; Marshall, Anne ; Krause, Carol ; Li, Yu-Wen ; Fitzgerald, Lawrence ; Miller, Keith
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 (CRF(1)) receptor antagonists. These CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research resulted in the discovery of compound 13-15, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 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.