Article
Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors
Registro en:
KÜMMERLE, Arthur E. et al. 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, v.55, p.7525-7545, 2012.
0022-2623
10.1021/jm300514y
1520-4804
Autor
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.
Resumen
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. 2030-01-01