- CHEMICAL COMPOUNDS FOR COATING OF NANOSTRUCTURES
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The present application relates to a chemical compound comprising an aromatic core, or a carbocyclic, non-aromatic, core, wherein the aromatic core is a benzene ring or a biphenyl; the carbocyclic, non-aromatic core is a 5 to 7 membered ring. The core has
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Page/Page column 47; 48
(2018/08/03)
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- 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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- An expedient strategy for the diversity-oriented synthesis of macrocyclic compounds with natural product-like characteristics
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Naturally-derived macrocyclic compounds are associated with a diverse range of biological activities, including antibacterial effects, and there are over 100 marketed macrocycle drugs derived from natural products. However, synthetic macrocycles are widely considered to be poorly explored in antibiotic development (indeed, within drug discovery in general). This has been attributed to challenges associated with the generation of such compounds. Whilst there are synthetic methods that can produce large collections of structurally similar macrocycles (i.e., compounds with varying appendages based around similar core macrocyclic ring architectures) there is a relative dearth of strategies for the efficient generation of more structurally diverse macrocycle collections in which there is greater variation in the nature of macrocyclic scaffolds present. Such macrocycle collections should contain compounds with a broad range of biological activities (including antibacterial activities) and the requisite robust synthetic methodology useful for analogue synthesis and lead optimization once an active compound has been identified in a biological screen. Herein, we describe a new and expedient diversity-oriented synthesis (DOS) strategy for the generation of a library of novel structurally diverse macrocyclic compounds with a high level of scaffold diversity. The strategy is concise, proceeds from readily-available starting materials, is modular in nature and features a variety of macrocyclisation techniques. In this proof-of-concept study, the synthesis of several previously unreported macrocyclic compounds was achieved. Each of these macrocycles was based around a distinct molecular scaffold and contained natural product-like structural features (e.g., three-dimensionality and multiple hydrogen bond donors and acceptors) as well as synthetic handles for potential further elaboration. The successful generation of these macrocycles demonstrates the feasibility of the new DOS strategy as a synthetic platform for library generation.
- Ciardiello, Joe J.,Galloway, Warren R.J.D.,O'Connor, Cornelius J.,Sore, Hannah F.,Stokes, Jamie E.,Wu, Yuteng,Spring, David R.
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p. 3567 - 3578
(2016/07/06)
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- Structure-Based Design of 3-(4-Aryl-1H-1,2,3-triazol-1-yl)-Biphenyl Derivatives as P2Y14 Receptor Antagonists
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UDP and UDP-glucose activate the P2Y14 receptor (P2Y14R) to modulate processes related to inflammation, diabetes, and asthma. A computational pipeline suggested alternatives to naphthalene of a previously reported P2Y14R antagonist (3, PPTN) using docking and molecular dynamics simulations on a hP2Y14R homology model based on P2Y12R structures. By reevaluating the binding of 3 to P2Y14R computationally, two alternatives, i.e., alkynyl and triazolyl derivatives, were identified. Improved synthesis of fluorescent antagonist 4 enabled affinity quantification (IC50s, nM) using flow cytometry of P2Y14R-expressing CHO cells. p-F3C-phenyl-triazole 65 (32) was more potent than a corresponding alkyne 11. Thus, additional triazolyl derivatives were prepared, as guided by docking simulations, with nonpolar aryl substituents favored. Although triazoles were less potent than 3 (6), simpler synthesis facilitated further structural optimization. Additionally, relative P2Y14R affinities agreed with predicted binding of alkynyl and triazole analogues. These triazoles, designed through a structure-based approach, can be assessed in disease models.
- Junker, Anna,Balasubramanian, Ramachandran,Ciancetta, Antonella,Uliassi, Elisa,Kiselev, Evgeny,Martiriggiano, Chiara,Trujillo, Kevin,Mtchedlidze, Giorgi,Birdwell, Leah,Brown, Kyle A.,Harden, T. Kendall,Jacobson, Kenneth A.
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supporting information
p. 6149 - 6168
(2016/07/26)
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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 48
(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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