Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors.

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.

Journal of medicinal chemistry 2012 Sep 13

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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.

Citation

Arthur E Kümmerle, Martine Schmitt, Suzana V S Cardozo, Claire Lugnier, Pascal Villa, Alexandra B Lopes, Nelilma C Romeiro, Hélène Justiniano, Marco A Martins, Carlos A M Fraga, Jean-Jacques Bourguignon, Eliezer J Barreiro. Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors. Journal of medicinal chemistry. 2012 Sep 13;55(17):7525-45