Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors.
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.
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.
Arthur E
AE
Kümmerle
Martine
M
Schmitt
Suzana V S
SV
Cardozo
Claire
C
Lugnier
Pascal
P
Villa
Alexandra B
AB
Lopes
Nelilma C
NC
Romeiro
Hélène
H
Justiniano
Marco A
MA
Martins
Carlos A M
CA
Fraga
Jean-Jacques
JJ
Bourguignon
Eliezer J
EJ
Barreiro
D000284:Administration, Oral; D000818:Animals; D015195:Drug Design; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011014:Pneumonia / Q000188:drug therapy
D006835:Hydrazones; D058988:Phosphodiesterase 4 Inhibitors