PDE4 inhibitors: a review of current developments (2005 – 2009)

Abstract

Background: Despite the sound preclinical database and some promising data from clinical trials, development of PDE4 inhibitors for the treatment of inflammatory or neurological diseases has been hampered by dose-limiting class-related side effects. Objective: In the past years, companies opted for different approaches to improve the therapeutic window of their compounds including topical administration of PDE4 inhibitors with the goal of minimizing systemic exposure. This change in strategy is reflected by the disclosure of novel and chemically diverse molecules that demonstrate the continued interest of pharmaceutical industry in developing PDE4 inhibitors. Conclusion: This review summarizes the clinical development of PDE4 inhibitors since 2005 and the associated patent literature with a focus on strategies applied to minimize systemic adverse effects. In sum, although a significant number of new drugs designed for improved tolerability entered clinical trials, so far none of them fulfilled expectations and best progress has been achieved recently with the oral, non-isoform selective PDE4 inhibitor roflumilast.

Keywords::

• asthma
• atopic dermatitis
• chronic obstructive pulmonary disease
• inhalation
• PDE4
• psoriasis
• respiratory disease
• rheumatoid arthritis

Acknowledgments

Special thanks to J Gràcia for stimulating discussions and help with the preparation of the manuscript.