An Overview of PDE4 Inhibitors in Clinical Trials: 2010 to Early 2022

Abstract

Since the early 1980s, phosphodiesterase 4 (PDE4) has been an attractive target for the treatment of inflammation-based diseases. Several scientific advancements, by both academia and pharmaceutical companies, have enabled the identification of many synthetic ligands for this target, along with the acquisition of precise information on biological requirements and linked therapeutic opportunities. The transition from pre-clinical to clinical phase was not easy for the majority of these compounds, mainly due to their significant side effects, and it took almost thirty years for a PDE4 inhibitor to become a drug i.e., Roflumilast, used in the clinics for the treatment of chronic obstructive pulmonary disease. Since then, three additional compounds have reached the market a few years later: Crisaborole for atopic dermatitis, Apremilast for psoriatic arthritis and Ibudilast for Krabbe disease. The aim of this review is to provide an overview of the compounds that have reached clinical trials in the last ten years, with a focus on those most recently developed for respiratory, skin and neurological disorders.

Emerging Potential of the Phosphodiesterase (PDE) Inhibitor Ibudilast for Neurodegenerative Diseases: An Update on Preclinical and Clinical Evidence

“…In mammals, the PDEs superfamily is classified into eleven families, known as PDE1—PDE11. These different families vary in their kinetic characteristics, distribution in various tissues, response to molecular regulators and co-factors (Ca 2+ , cGMP, Zn 2+ and Mg 2+ ), specificity for synthetic PDE inhibitors and occasionally their specificity for substrates (cAMP or cGMP) [ 38 , 39 ]. Each PDE family is encoded by one or multiple genes, and alternative mRNA splicing results in several splice variants [ 39 ].…”

“…To date, more than fifty PDEs have been identified in humans. A numeral following PDE indicates the specific family (e.g., PDE4), the capital letter that follows indicates the gene (e.g., PDE4D), while a numeral at the end shows the splice variant [ 38 , 40 ]. PDEs are widely expressed in human tissues including the CNS [ 41 ].…”

“…PDEs are majorly implicated in multiple signaling pathways, by reducing the intracellular levels of cAMP and cGMP [ 42 ]. In particular, PDEs can catalyze the hydrolysis of the phosphodiester bond of cAMP and cGMP, leading to the production of the inactive AMP and GMP [ 38 ]. PDE inhibition can result in increased levels of cyclic nucleotides, which regulate several cellular functions, acting as secondary messengers [ 38 ].…”

“…In particular, PDEs can catalyze the hydrolysis of the phosphodiester bond of cAMP and cGMP, leading to the production of the inactive AMP and GMP [ 38 ]. PDE inhibition can result in increased levels of cyclic nucleotides, which regulate several cellular functions, acting as secondary messengers [ 38 ]. Cyclic nucleotides are majorly implicated in the transcriptional regulation via the cAMP response element-binding protein (CREB) [ 43 ].…”

“…Based on this promising in vitro and in vivo evidence, MK0952, a PDE4 inhibitor, had been tested for patients with mild-to-moderate AD in a phase 2 randomized clinical trial (NCT00362024). In AD, zatomilast has been investigated in phase 1 clinical trials (NCT02648672, NCT02840279, NCT03030105) as well as in a phase 2 clinical trial (NCT03817684) [ 38 , 62 ]. A randomized, placebo-controlled phase 4 clinical trial has been completed, which aimed to evaluate the efficacy of cilostazol in AD patients (mild-to-moderate stages) with subcortical white matter hyperintensities (WMHI) treated with donepezil (NCT01409564).…”