Abstract:
:This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discovery of analogue 12-3, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 4.7 +/- 2.0 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 12-3 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 12-3 has been advanced to clinical trials.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Gilligan PJ,He L,Clarke T,Tivitmahaisoon P,Lelas S,Li YW,Heman K,Fitzgerald L,Miller K,Zhang G,Marshall A,Krause C,McElroy J,Ward K,Shen H,Wong H,Grossman S,Nemeth G,Zaczek R,Arneric SP,Hartig P,Robertson DW,Tdoi
10.1021/jm9000242subject
Has Abstractpub_date
2009-05-14 00:00:00pages
3073-83issue
9eissn
0022-2623issn
1520-4804journal_volume
52pub_type
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