Phosphodiesterase-4 inhibitors: a review of current developments (2010 - 2012)

At last, after many years of research, roflumilast has become the first oral phosphodiesterase-4 inhibitor to be approved by the medical agencies as an add-on therapy for chronic obstructive pulmonary disease. A second compound, apremilast is targeted for submission of new drug application for the treatment of psoriasis in the second half of 2013. These compounds represent a breakthrough and a reward in the field after the many failures to date in clinical development.

This review summarizes the clinical development of PDE4 inhibitors from 2010 - 2012 and the associated patent literature with a focus on strategies to overcome the common pitfalls of oral PDE4 inhibitors.

In the last few years, influenced by the body of published clinical data, many companies have lost interest in PDE4 as a target. Many of those that have persevered have opted to realign their research programs either toward compounds specifically designed for inhaled delivery or in search of an increase in clinical efficacy by combining two mechanisms in a single compound. This change is reflected by the continued disclosure of novel and chemically diverse molecules, indicating for some in the pharmaceutical industry that all is not yet lost.