Pharmacophore-driven design and biological evaluation of heterocyclic PDE4B inhibitors for Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative condition marked by a gradual loss of cognitive function, impaired synaptic signalling, and sustained neuroinflammatory responses. Among the molecular pathways associated with disease progression, cyclic adenosine monophosphate (cAMP) signalling, plays a crucial factor in disruption of cellular homeostasis. Phosphodiesterase-4 (PDE4), especially the PDE4B isoform, controls intracellular cAMP levels in neuronal and glial cells, which affects inflammatory signalling and synaptic plasticity in the brain. Therefore, selectively targeting PDE4B is a novel approach to identify the small molecule's therapeutic activity to restore the cAMP signalling, with parallel regulation of the dose-limiting side effects. GSK356278 and Rolipram are the known PDE4B modulators, which have been considered for the current study to generate significant pharmacophoric features and execute drug design as CNS-active PDE4B inhibitors. Six heterocyclic derivatives were designed and synthesised by altering the core scaffold in order to maximise hydrophobicity, CNS permeability, and Q-pocket engagement without depending on direct Zn2+ or Mg2+ coordination. Among these, molecule VCHH-19 and VCPH-19 demonstrated significant CNS compatibility and good binding stability. PC12 cell lines were chosen to verify the in vitro neuroprotective response, and the Drosophila model for in vivo for AD assessment. All of these results indicated the significance of pyridine-based heterocycles molecules as potential candidates for PDE4B-targeted AD treatment.