Design of 2,5-Dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and Structure−Activity Relationships of a Series of Potent and Orally Active Corticotropin-Releasing Factor Receptor Antagonists

• DOI: 10.1021/jm040058e
• Publication Date: 2004-09-02T11:40:53Z
• Authors: Chen; Keith M. Wilcoxen; Charles Q. Huang; Yun-Feng Xie; James R. McCarthy; Thomas R. Webb; Yun-Fei Zhu; John Saunders; Xin-Jun Liu; Ta-Kung Chen; Haig Bozigian; Dimitri E. Grigor...
• Keywords: Lipophilicity; IC50

We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at 3-position bicyclic nucleus was designed to reduce lipophilicity from initial leads such as 7. Here, we showed these 3-pyridyl compounds exhibited CRF(1) Moreover, hydrophilic moiety increased water solubility some analogues. Compound 26 h good binding affinity receptor with K(i) value 3.5 nM. As functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing (IC(50) = 50 nM), ACTH release cultured rat pituitary 20 nM). had log P 4.9 greater than 10 mg/mL. Pharmacokinetic studies rats orally bioavailable able penetrate into brain. has been demonstrated vivo efficacy animal behavioral models measure anxiolytic activity. These results suggest analogues this proper physicochemical properties pharmacokinetic profiles. developed clinical compound patients major depression.