title: Phosphodiesterase-4 as a potential drug target.
abstract: Phosphodiesterase-4 (PDE4) is the predominant enzyme in some specific cell types that is responsible for the degradation of the second messenger, cAMP. Consequently, PDE4 plays a crucial role in cell signalling and, as such, it has been the target of clinical drug development of various indications, ranging from anti-inflammation to memory enhancement. In this review, the fundamental biological role of PDE4 in intracellular signalling, its tissue distribution and regulation are described. The historical development of various chemical classes of PDE4 inhibitors and the challenges that face these inhibitors as therapeutics are also discussed. Finally, recent advances in the structural biology of PDE4 and their complexes with various inhibitors, as well as its potential impact on the rational design of potent and selective PDE4 inhibitors, are presented.
authors.affiliation: Plexxikon, Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA. kzhang@plexxikon.com
authors.forename: Kam Y J
authors.initials: KY
authors.lastname: Zhang
authors.forename: Prabha N
authors.initials: PN
authors.lastname: Ibrahim
authors.forename: Sam
authors.initials: S
authors.lastname: Gillette
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007424:Intracellular Fluid / Q000201:enzymology; D009928:Organ Specificity / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4