Recent developments of phosphodiesterase inhibitors: Clinical trials, emerging indications and novel molecules

Abstract

The phosphodiesterase (PDE) enzymes, key regulator of the cyclic nucleotide signal transduction system, are long-established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a particularly high number of clinical trials involving PDE inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 87 agents with PDE-inhibiting capacity, of which 85 interact with PDE enzymes as primary target. We provide an overview of the clinical drug development with focus on the current clinical uses, novel molecules and indications, highlighting relevant clinical studies. We found that the bulk of current clinical uses for this class of therapeutic agents are chronic obstructive pulmonary disease (COPD), vascular and cardiovascular disorders and inflammatory skin conditions. In COPD, particularly, PDE inhibitors are characterised by the compliance-limiting adverse reactions. We discuss efforts directed to appropriately adjusting the dose regimens and conducting structure-activity relationship studies to determine the effect of structural features on safety profile. The ongoing development predominantly concentrates on central nervous system diseases, such as schizophrenia, Alzheimer's disease, Parkinson's disease and fragile X syndrome; notable advancements are being also made in mycobacterial infections, HIV and Duchenne muscular dystrophy. Our analysis predicts the diversification of PDE inhibitors' will continue to grow thanks to the molecules in preclinical development and the ongoing research involving drugs in clinical development.

Keywords: PDE inhibition; apremilast; cyclic nucleotides; ibudilast; roflumilast; second messengers; sildenafil.

FIGURE 1

Schematic structure of PDE enzymes. This figure schematically presents principle structural features of the individual PDE isoforms. The PDE families are grouped according to the cyclic nucleotide affinities. The structural features and approximate isoform sizes of each PDE family are summarized as per (Baillie et al., 2019; Conti and Beavo, 2007; Francis et al., 2011; Maurice et al., 2014). Abbreviations: cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; PDE, phosphodiesterase; GAF, cGMP-binding PDEs, Anabaena adenylyl cyclase, and Escherichia coli FhlA; UCR, upstream conserved region; CaM; calmodulin; REC, signal regulatory domain; PAS, Per-ARNT-Sim; Pat7, 7-residue nuclear localization signal.

FIGURE 2

Marketed and investigational PDE inhibitors mapped to the human PDE proteins. This figure illustrates the phylogenetic relationship between the human PDE isoforms and maps the identified marketed and investigational agents to their targets. The amino acid sequences of each for each of the human PDE proteins were obtained from UniProt (UniProtKB database) (UniProt Consortium, 2021). Multiple sequence alignment was performed using Clustal Omega (RRID:SCR_001591). The phylogenetic tree was visualized in R Studio (Paradis and Schliep, 2019; Yu, 2020) and annotated in Adobe Illustrator CC 22.1.