A Comprehensive Review of Phosphodiesterases 4 (PDE4) Inhibitors in Clinical Trials

Phosphodiesterase 4 (PDE4) facilitates the enzymatic breakdown of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), through its four distinct isotypes, namely PDE4A to PDE4D, along with more than 25 splice variants. It plays a crucial role in cancer development, respiratory issues such as asthma and chronic obstructive pulmonary disease (COPD), autoimmune diseases like psoriasis, and neurological disorders such as Alzheimer's disease. Various methods are being developed to enhance clinical efficacy and reduce side effects. Some of these methods include drug delivery via inhalation and the development of non-emetic PDE4 inhibitors and mixed PDE inhibitors. These inhibitors offer several advantages over traditional formulations, including selectivity for specific inhibitors, targeted tissue distribution, and oral effectiveness. All these efforts have led to the emergence of novel PDE4 inhibitors, with some having progressed to clinical trial stages and others approved as medications. This review summarises PDE4 inhibitors currently in clinical trials, highlighting their therapeutic potential, limitations, and future prospects.