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

• 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
• ISSN: 0022-2623; 1520-4804
• 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-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.