Novel Pyrrolidine Derivatives of Budesonide as Long Acting Inhaled Corticosteroids for the Treatment of Pulmonary Inflammatory Diseases

Inhaled
corticosteroids (ICSs) represent the first line therapy for the treatment
of asthma and are also extensively utilized in chronic obstructive
pulmonary disease. Our goal was to develop a new ICS with a basic
group, which can allow solid state feature modulation, achieving at
the same time high local anti-inflammatory effect and low systemic
exposure. Through a rational drug design approach, a new series of
pyrrolidine derivatives of budesonide was identified. Within the series,
several compounds showed nanomolar binding affinity (Ki) with GR that mostly correlated with the effect in inducing
GR nuclear translocation in CHO cells and anti-inflammatory effects
in macrophagic cell lines. Binding and functional cell-based assays
allowed identifying compound 17 as a potent ICS agonist
with a PK profile showing an adequate lung retention and low systemic
exposure in vivo. Finally, compound 17 proved to be more
potent than budesonide in a rat model of acute pulmonary inflammation.