Design, synthesis, and pharmacological evaluation of N-acylhydrazones and novel conformationally constrained compounds as selective and potent orally active phosphodiesterase-4 inhibitors.

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Kummerle AE, Schmitt M, Cardozo SV, Lugnier C, Villa P, Lopes AB, Romeiro NC, Justiniano H, Martins MA, Fraga CA, Bourguignon JJ, Barreiro EJ

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. Epub 2012 Aug 30.

PubMed ID
22891752 [ View in PubMed
]
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-alpha 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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
(R)-RolipramcAMP-specific 3',5'-cyclic phosphodiesterase 4BIC 50 (nM)231N/AN/ADetails
(R)-RolipramcAMP-specific 3',5'-cyclic phosphodiesterase 4DIC 50 (nM)622N/AN/ADetails
ZardaverinecAMP-specific 3',5'-cyclic phosphodiesterase 4DIC 50 (nM)800N/AN/ADetails