PDE4B Inhibition: Exploring the Landscape of Chemistry Behind Specific PDE4B Inhibitors, Drug Design, and Discovery

Phosphodiesterase 4 (i.e., PDE4A, PDE4B, PDE4C, and PDE4D) is an enzyme group that regulates intracellular cyclic adenosine monophosphate (cAMP) levels, which are involved in multiple physiological activities. PDE4B and PDE4D have closely identical amino acid sequences (~80%) and are highly expressed due to increases in cAMP levels and other factors like hormones, neurotransmitters, etc. Thus, selective PDE4B suppression and discovery of its inhibitors are quite challenging. The PDE4B isoform, highly expressed in inflammatory disorders, cancers, cognitive and metabolic disorders, represents a potential target for therapy and drug discovery. PDE4B inhibition is what produces the positive therapeutic results, whereas nonselective PDE4D inhibition leads to unfavorable side effects. In the realm of modern research, selective PDE4B inhibition is important and ought to be achieved to improve the safety and effectiveness of its inhibitors. This article highlights the advances in the development of selective PDE4BIs during the past decade. The chemical architecture for selective inhibitors includes different functional groups capable of producing the essential interactions with the catalytic domain of PDE4B. The In Silico interaction analysis revealed the importance of PDE4BIs' interaction with the Q (PHE-446 and GLU-443), M (Zn²⁺ and Mg²⁺), and S pockets, along with the CR3 domain of the enzyme. Additionally, a few of the natural products and their derivatives are also being explored as PDE4BIs. Dual activities of the PDE4BIs, i.e., PDE4B inhibition along with TRPA1 and M₃ inhibition and β₂ activation, are the future perspective for the treatment of inflammatory diseases like psoriasis, chronic obstructive pulmonary disease (COPD), asthma, autoimmune disorders, etc.