Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure–Activity Relationships

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.