Design, Synthesis, and Pharmacological Evaluation of N-Acylhydrazones and Novel Conformationally Constrained Compounds as Selective and Potent Orally Active Phosphodiesterase-4 Inhibitors
Design, Synthesis, and Pharmacological Evaluation of N-Acylhydrazones and Novel Conformationally Constrained Compounds as Selective and Potent Orally Active Phosphodiesterase-4 Inhibitors
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DOI：
10.1021/jm300514y
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发表时间：
2012-09-13
影响因子：
7.3
通讯作者：
Barreiro, Eliezer J.
中科院分区：
文献类型：
--
作者：
Kuemmerle, Arthur E.;Schmitt, Martine;Barreiro, Eliezer J.
在一小系列测试的N-酰基腙（NAH）中，选择化合物8a作为选择性亚微摩尔磷酸二酯酶-4（PDE 4）抑制剂，其与体外和体内测量的抗TNF-α性质相关。化合物8a的识别模式通过分子建模研究阐明，基于扎达维林的3D结构的知识，扎达维林是一种类似于8a结构的PDE 4抑制剂，与PDE 4共结晶。基于对N-甲基-NAH的进一步构象分析，喹唑啉衍生物（19）被设计为构象受限的NAH类似物，并且与8a相比显示出相似的体外药理学特征。此外，当在LPS诱发的气道高反应性中口服测试时，发现19是活性的，并且完全证实了支持这项工作的工作假设。
Among a small series of tested N-acylhydrazones (NAHs), the compound 8a was selected as a selective submicromolar phosphodiesterase-4 (PDE4) inhibitor associated with anti-TNF-alpha properties measured both in vitro and in vivo. The recognition pattern of compound 8a was elucidated through molecular modeling studies based on the knowledge of the 3D-structure of zardaverine, a PDE4 inhibitor resembling the structure of 8a, cocrystallized with the PDE4. Based on further conformational analysis dealing with N-methyl-NAHs, a quinazoline derivative (19) was designed as a conformationally constrained NAH analogue and showed similar in vitro pharmacological profile, compared with 8a. In addition 19 was found active when tested orally in LPS-evoked airway hyperreactivity and fully confirmed the working hypothesis supporting this work.