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首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis and Pharmacological Characterization of Novel Druglike Corticotropin-Releasing Factor 1 Antagonists
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Synthesis and Pharmacological Characterization of Novel Druglike Corticotropin-Releasing Factor 1 Antagonists

机译：新型类药物促肾上腺皮质激素释放因子1拮抗剂的合成与药理特性

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摘要

To identify new CRF1 receptor antagonists, an attempt to modify the bis-hetherocycle moiety present in the top region of the dihydropirrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF1 receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic hetherocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.
机译：为了鉴定新的CRF1受体拮抗剂，根据CRF1受体拮抗剂结合口袋的新药效学假说，尝试修饰存在于二氢吡咯[2,3]吡啶模板顶部区域的双-杂环部分。特别地，存在于先前系列化合物中的2-噻唑环被更具亲水性的非芳香族杂环所取代，该杂环能够与氨基酸残基Thr192和Tyr195进行适当的H键相互作用。这项探索，然后再对芳基侧链的取代进行精确分析，从而能够鉴定出在啮齿动物和灵长类动物的焦虑动物模型中均具有出色的药代动力学和出色的体内活性的体外有效化合物。

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