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

Abstract

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.

Novel selective PDE type 1 inhibitors cause vasodilatation and lower blood pressure in rats

“…At high concentrations (10 μM), which are far above the nM concentrations of Lu AF41228 and Lu AF58027 inhibiting the PDE1 enzymes, we would suggest that these relaxations to Lu AF41228 and Lu AF58027 which were insensitive to ODQ and SQ22536 may be mediated by off‐target effects. Thus, biphenyl pyridazinone derivatives which inhibit PDE4 were described to have affinity for adenosine receptors (Gracia et al , ) and, in our work, screening also revealed that Lu AF41228 at a high concentration (10 μM) binds to several adenosine receptor subtypes.…”

Inhaled Phosphodiesterase 4 (PDE4) Inhibitors for Inflammatory Respiratory Diseases

“…Almirall most recently published on two potent chemical series, the naphthyridinones (represented by compound 72, IC 50 = 0.17 nM) (Roberts et al, 2018) and pyridazinones (represented by compound 50, IC 50 = 0.05 nM) (Gracia et al, 2016). The compounds are not planned to advance past preclinical development.…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…Compounds 74 and 75 were identified as potent, long‐acting, and potentially safe inhaled PDE4 inhibitors. Compound 76 bearing a 1,6‐naphthyridin‐5(6 H)‐one N‐oxide moiety was the most potent derivative of 73 , with IC 50 of 45 pM in enzymatic assay and 75 pM in cellular assay …”