2. Academic Validation
  3. 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

  • J Med Chem. 2012 Sep 13;55(17):7525-45. doi: 10.1021/jm300514y.
Arthur E Kümmerle 1,  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
Affiliations

Affiliation

  • 1 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.
PMID: 22891752 DOI: 10.1021/jm300514y
Abstract

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.

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