186772-44-1Relevant articles and documents
Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure-Activity Relationships
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
, p. 10479 - 10497 (2016/12/16)
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.
m-Diethynylbenzene macrocycles: Syntheses and self-association behavior in solution
Tobe, Yoshito,Utsumi, Naoto,Kawabata, Kazuya,Nagano, Atsushi,Adachi, Kiyomi,Araki, Shunji,Sonoda, Motohiro,Hirose, Keiji,Naemura, Koichiro
, p. 5350 - 5364 (2007/10/03)
m-Diethynylbenzene macrocycles (DBMs), buta-1,3-diyne-bridged [4n]metacyclophanes, have been synthesized and their self-association behaviors in solution were investigated, Cyclic tetramers, hexamers, and octamers of DBMs having exo-annular octyl, hexadecyl, and 3,6,9-trioxadecyl ester groups were prepared by intermolecular oxidative coupling of dimer units or intramolecular cyclization of the corresponding open-chain oligomers. The aggregation properties were investigated by two methods, the 1H NMR spectra and the vapor pressure osmometry (VPO). Although some discrepancies were observed between the association constants obtained from the two methods, the qualitative view was consistent with each other. The analysis of self-aggregation by VPO revealed unique aggregation behavior of DBMs in acetone and toluene, which was not elucidated by the NMR method. Namely, the association constants for infinite association are several times larger than the dimerization constant, suggesting that the aggregation is enhanced by the formation of dimers (a nucleation mechanism). In polar solvents, DBMs aggregate more strongly than in chloroform due to the solvophobic interactions between the macrocyclic framework and the solvents. Moreover, DBMs self-associate in aromatic solvents such as toluene and o-xylene more readily than in chloroform. In particular, the hexameric DBM having a large macrocyclic cavity exhibits extremely large association constants in aromatic solvents. By comparing the aggregation properties of DBMs with the corresponding acyclic oligomers, the effect of the macrocyclic structure on the aggregation propensity was clarified. Finally, it turned out that DBMs tend to aggregate more readily than the corresponding phenylacetylene macrocycles, acetylene-bridged [2n]metacyclophanes, owing to the withdrawal of the electron density from the aromatic rings by the butadiyne linkages which facilitates π-π stacking interactions.
