3 research outputs found
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 (<i>K</i><sub>i</sub>) 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 <b>17</b> as a potent ICS agonist
with a PK profile showing an adequate lung retention and low systemic
exposure in vivo. Finally, compound <b>17</b> proved to be more
potent than budesonide in a rat model of acute pulmonary inflammation
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 (<i>K</i><sub>i</sub>) 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 <b>17</b> as a potent ICS agonist
with a PK profile showing an adequate lung retention and low systemic
exposure in vivo. Finally, compound <b>17</b> proved to be more
potent than budesonide in a rat model of acute pulmonary inflammation
Discovery and Optimization of Thiazolidinyl and Pyrrolidinyl Derivatives as Inhaled PDE4 Inhibitors for Respiratory Diseases
Phosphodiesterase
4 (PDE4) is a key cAMP-metabolizing enzyme involved
in the pathogenesis of inflammatory disease, and its pharmacological
inhibition has been shown to exert therapeutic efficacy in chronic
obstructive pulmonary disease (COPD). Herein, we describe a drug discovery
program aiming at the identification of novel classes of potent PDE4
inhibitors suitable for pulmonary administration. Starting from a
previous series of benzoic acid esters, we explored the chemical space
in the solvent-exposed region of the enzyme catalytic binding pocket.
Extensive structural modifications led to the discovery of a number
of heterocycloalkyl esters as potent <i>in vitro</i> PDE4
inhibitors. (<i>S</i>*,<i>S</i>**)-<b>18e</b> and (<i>S</i>*,<i>S</i>**)-<b>22e</b>,
in particular, exhibited optimal <i>in vitro</i> ADME and
pharmacokinetics properties and dose-dependently counteracted acute
lung eosinophilia in an experimental animal model. The optimal biological
profile as well as the excellent solid-state properties suggest that
both compounds have the potential to be effective topical agents for
treating respiratory inflammatory diseases