Small-molecule inhibitors of PDE-IV and -VII in the treatment of respiratory diseases and chronic inflammation.
Targeting phosphodiesterase IV (PDE-IV) with small-molecule inhibitors as a therapeutic for chronic inflammatory disorders has been an active area of research interest for many years. The major drawback, however, has been to develop pharmacophores that would differentiate between targeting isoforms of PDE-IV associated with inflammation, as opposed to those that cause emesis, a major side effect associated with PDE-IV inhibition. Several different approaches have been employed, including designing subtype selective PDE-IV inhibitors. A recent approach has been to develop chemotypes that target PDE-VII, a cAMP-specific PDE, expressed widely in immune and pro-inflammatory cells. It is hypothesized that dual inhibitors, which function to inhibit both PDE-IV and VII, may achieve a higher therapeutic index and thereby exhibit a lower propensity to cause adverse side effects that are characteristic when targeting PDE-IV alone. This review focuses on the major classes of compounds that are presently being studied for their potential to inhibit PDE-VII and discusses the available data in the development of dual PDE-IV and -VII inhibitors, their biologic activity and their scope as a therapeutic choice in chronic inflammatory diseases.
Vijayakrishnan
Lalitha
L
Ranbaxy Laboratories Ltd, Department of Pharmacology, New Drug Discovery Research (R & D III), Plot No. 20, Sector-18, Gurgaon-122 001, India. Lalitha.vijayakrishnan@ranbaxy.com
Rudra
Sonali
S
Eapen
Mathew S
MS
Dastidar
Sunanda
S
Ray
Abhijit
A
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002908:Chronic Disease; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*
D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7