期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 11, 页码 5380-5390出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm300323t
关键词
-
资金
- King Pharmaceuticals, Inc., Research and Development, NC
A relevant problem of the pyrazolo[4,3-e]-[1,2,4]triazolo[1,5-c]pyrimidine nucleus, an attractive scaffold for the preparation of adenosine receptor antagonists, is the low water solubility. We originally functionalized the C-5 position with a salifiable 4-pyridylcarbamoyl moiety that conferred good water solubility at low pH (<4.0) but poor solubility at physiologic pH, indicative of the dissociation of the pyridinium species. Here we replaced the pyridin-4-yl moiety with a 1-(substituted)piperidin-4-yl ring to exploit the higher basicity of this nucleus and for the the possibility to generate stable, water-soluble salts. The hydrochloride salt of the 1-(cyclohexylmethyl)piperidin-4-yl derivative (10, K-i(hA(3)) = 9.7 nM, IC50(hA(3)) = 30 nM, K-i(hA(1)/hA(3)) = 351, K-i(hA(2A)/hA(3)) > 515, IC50(HA(2B)) > 5 mu M) showed a solubility of 8 mg/mL at physiological pH and gave a stable aqueous system suitable for, intravenous infusion. Molecular modeling studies were helpful in rationalizing the available structure-activity relationships and the selectivity profile of the new ligands.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据