- Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure-Activity Relationships
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Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent-filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century MicroSprayer Aerosolizer.
- Gràcia, Jordi,Buil, Maria Antonia,Castro, Jordi,Eichhorn, Peter,Ferrer, Manel,Gavaldà, Amadeu,Hernández, Bego?a,Segarra, Victor,Lehner, Martin D.,Moreno, Imma,Pagès, Lluís,Roberts, Richard S.,Serrat, Jordi,Sevilla, Sara,Taltavull, Joan,Andrés, Miriam,Cabedo, Judit,Vilella, Dolors,Calama, Elena,Carcasona, Carla,Miralpeix, Montserrat
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p. 10479 - 10497
(2016/12/16)
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- 3-(5-Amino-6-oxo-1,6-dihydropyridazin-3-yl)-biphenyl derivatives as PDE4 inhibitors
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New pyridazin-3(2H)-one derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of the phosphodiesterase IV (PDE4).
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- (3-oxo)pyridazin-4-ylurea derivatives as PDE4 inhibitors
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New (3-oxo)pyridazin-4-ylurea derivatives having the chemcial structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of the phosphodiesterase IV (PDE4).
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Page/Page column 42; 43
(2010/07/03)
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- Oligofunctional amphiphiles featuring geometric core group preorganization: Synthesis and study of Langmuir and Langmuir-Blodgett films
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Based on the principle of supramolecular preorganization, a new type of oligofunctional amphiphile, of which compounds 1-4 are representative structures, has been designed and synthesized. The typical feature of their structure is a highly rigid and geometrically well-defined central unit composed of ethynylene substituted aromatic spacers with different numbers of amphiphilic segment groups (also of a rigid geometric design) attached to it. The molecules form well-defined Langmuir films when spread from a solution at the air/water interface or when a 10-4 M aqueous CaCl2 solution was used as the subphase. By analysis of the surface pressure-surface area (π-A) isotherms, information on the packing behavior and orientation of the amphiphilic molecules depending on the molecular structure could be obtained. Morphological characterization of the dynamic process of monolayer compression at the air/water interface was carried out by Brewster angle microscopy, illustrating several phase states visualized as snap shots. Thin monolayer films produced on a 10-4 M aqueous CaCl2 subphase can be transferred to a mica solid support by the Langmuir-Blodgett technique. Tapping mode atomic force microscopy reveals a surface topography of the monofilms composed of 1 and 3 that differ in roughness and also in the properties of elasticity, hardness and adhesive strength. X-Ray crystal structure analysis of three relevant intermediate compounds of the synthesis were successfully determined giving an indication of the potential structural features inherent in the new amphiphiles. The Royal Society of Chemistry 2005.
- Mueller, Petra U.,Weber, Edwin,Rheinwald, Gerd,Seichter, Wilhelm
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p. 3757 - 3766
(2007/10/03)
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