title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Almirall R&D Centre, Department of Medicinal Chemistry, Laureà Miró 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Lluis.pages@almirall.com
authors.forename: Lluís
authors.initials: L
authors.lastname: Pagès
authors.forename: Amadeu
authors.initials: A
authors.lastname: Gavaldà
authors.forename: Martin D
authors.initials: MD
authors.lastname: Lehner
mesh_terms: D000631:Aminopyridines / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000009:adverse effects / Q000494:pharmacology; D002986:Clinical Trials as Topic; D003521:Cyclopropanes / Q000009:adverse effects / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D009422:Nervous System Diseases / Q000188:drug therapy / Q000503:physiopathology; D010330:Patents as Topic; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast