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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- 作者：Arthur E. K眉mmerle ; Martine Schmitt ; Suzana V. S. Cardozo ; Claire Lugnier ; Pascal Villa ; Alexandra B. Lopes ; Nelilma C. Romeiro ; H茅l猫ne Justiniano ; Marco A. Martins ; Carlos A. M. Fraga ; Jean-Jacques Bourguignon ; Eliezer J. Barreiro
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：September 13, 2012
- 年：2012
- 卷：55
- 期：17
- 页码：7525-7545
- 全文大小：770K
- 年卷期：v.55,no.17(September 13, 2012)
- ISSN：1520-4804
文摘
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-伪 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.