Laboratório de Avaliacão e Síntese de Substâncias Bioativas (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro , Rio de Janeiro 68023, RJ 21944-971, Brazil.
J Med Chem. 2012 Sep 13;55(17):7525-45. doi: 10.1021/jm300514y. Epub 2012 Aug 30.
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-α 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.
在一系列经过测试的 N-酰腙（NAHs）中，选择化合物 8a 作为一种选择性亚毫摩尔磷酸二酯酶-4（PDE4）抑制剂，该抑制剂具有抗 TNF-α 特性，在体外和体内均有测量。通过基于扎达维林（一种与 8a 结构相似的 PDE4 抑制剂）的 3D 结构的知识的分子建模研究，阐明了化合物 8a 的识别模式，该抑制剂与 PDE4 共结晶。基于进一步涉及 N-甲基-NAHs 的构象分析，设计了一种喹唑啉衍生物（19）作为构象受限的 NAH 类似物，并且与 8a 相比，表现出相似的体外药理学特征。此外，在 LPS 诱发的气道高反应性的体内试验中，19 被证明具有活性，完全证实了支持这项工作的工作假说。
