Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and structure-activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists
Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and structure-activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists
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DOI：
10.1021/jm040058e
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发表时间：
2004-09-09
影响因子：
7.3
通讯作者：
Grigoriadis, DE
中科院分区：
文献类型：
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作者：
Chen, C;Wilcoxen, KM;Grigoriadis, DE
我们以前已经表明，3-苯基吡唑并[1，5-a]嘧啶8的例子是有效的拮抗剂的人促肾上腺皮质激素释放因子-1受体。设计了一系列在双环核的3位含有弱碱性吡啶环的3-吡啶基吡唑并[1，5-a]嘧啶15、25-30、34和35，以降低起始先导化合物如7的亲脂性。在这里，我们表明，这些3-吡啶基化合物在人CRF 1，受体表现出有效的拮抗剂。此外，亲水性和弱碱性吡啶部分增加了一些类似物的水溶性。化合物26 h对人CRF 1受体表现出良好的结合亲和力，Ki值为3.5 nM。作为一种功能性拮抗剂，其剂量依赖性地抑制表达CRF 1受体的细胞中CRF刺激的cAMP产生[IC 50 = 50 nM]，以及培养的大鼠垂体细胞中CRF刺激的ACTH释放[IC 50 = 20 nM]。26小时的log P值为4.9，水溶性大于10 mg/mL。大鼠药代动力学研究表明，26 h口服生物利用度，并能够渗透到大脑。在测量抗焦虑活性的动物行为模型中，已经证明了26 h的体内功效。这些结果表明，该系列类似物是有效的CRF 1受体拮抗剂，具有适当的理化性质和良好的药代动力学特征。26 h被开发成一种临床化合物，并在重度抑郁症患者中表现出疗效。
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 of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF1, receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26h exhibited good binding affinity at the human CRF1 receptor with a K-i value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF1 receptor [IC50 = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells [IC50 = 20 nM). 26h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26h was orally bioavailable and able to penetrate into the brain. 26h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF1, receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26h was developed into a clinical compound and exhibited efficacy in patients with major depression.