Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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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.

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.[1]

References

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, P.J., Clarke, T., He, L., Lelas, S., Li, Y.W., Heman, K., Fitzgerald, L., Miller, K., Zhang, G., Marshall, A., Krause, C., McElroy, J.F., Ward, K., Zeller, K., Wong, H., Bai, S., Saye, J., Grossman, S., Zaczek, R., Arneric, S.P., Hartig, P., Robertson, D., Trainor, G. J. Med. Chem. (2009) [Pubmed]

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