Design, Synthesis, and Pharmacological Evaluation of N-Acylhydrazones and Novel Conformationally Constrained Compounds as Selective and Potent Orally Active Phosphodiesterase-4 Inhibitors

作者：Kuemmerle Arthur E; Schmitt Martine; Cardozo Suzana V S; Lugnier Claire; Villa Pascal; Lopes Alexandra B; Romeiro Nelilma C; Justiniano Helene; Martins Marco A; Fraga Carlos A M; Bourguignon Jean Jacques; Barreiro Eliezer J^*

来源：Journal of Medicinal Chemistry, 2012, 55(17): 7525-7545.

DOI：10.1021/jm300514y

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.

• 出版日期2012-9-13