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 mod...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2012-09, Vol.55 (17), p.7525-7545
Main Authors: Kümmerle, Arthur E, Schmitt, Martine, Cardozo, Suzana V. S, Lugnier, Claire, Villa, Pascal, Lopes, Alexandra B, Romeiro, Nelilma C, Justiniano, Hélène, Martins, Marco A, Fraga, Carlos A. M, Bourguignon, Jean-Jacques, Barreiro, Eliezer J
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biochemistry, Molecular Biology
Cellular Biology
Drug Design
Female
Humans
Hydrazones - chemical synthesis
Hydrazones - chemistry
Hydrazones - pharmacology
Hydrazones - therapeutic use
Life Sciences
Magnetic Resonance Spectroscopy
Mass Spectrometry
Mice
Models, Molecular
Molecular Conformation
Phosphodiesterase 4 Inhibitors - chemical synthesis
Phosphodiesterase 4 Inhibitors - chemistry
Phosphodiesterase 4 Inhibitors - pharmacology
Phosphodiesterase 4 Inhibitors - therapeutic use
Pneumonia - drug therapy
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm300514y