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
Drug Target Property Measurement pH Temperature (°C) (R)-Rolipram cAMP-specific 3',5'-cyclic phosphodiesterase 4B IC 50 (nM) 231 N/A N/A Details (R)-Rolipram cAMP-specific 3',5'-cyclic phosphodiesterase 4D IC 50 (nM) 622 N/A N/A Details Zardaverine cAMP-specific 3',5'-cyclic phosphodiesterase 4D IC 50 (nM) 800 N/A N/A Details