A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.
A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.
A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases.
3′,5′-cyclic-nucleotide phosphodiesterases (EC 3.1.4.17) are a family of phosphodiesterases. Generally, these enzymes hydrolyze a nucleoside 3′,5′-cyclic phosphate to a nucleoside 5′-phosphate:
PDE3 is a phosphodiesterase. The PDEs belong to at least eleven related gene families, which are different in their primary structure, substrate affinity, responses to effectors, and regulation mechanism. Most of the PDE families are composed of more than one gene. PDE3 is clinically significant because of its role in regulating heart muscle, vascular smooth muscle and platelet aggregation. PDE3 inhibitors have been developed as pharmaceuticals, but their use is limited by arrhythmic effects and they can increase mortality in some applications.
Phosphodiesterase 1, PDE1, EC 3.1.4.1, systematic name oligonucleotide 5′-nucleotidohydrolase) is a phosphodiesterase enzyme also known as calcium- and calmodulin-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase (PDE1-PDE11). Phosphodiesterase 1 has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. The various isoforms exhibit different affinities for cAMP and cGMP.
cAMP-specific 3',5'-cyclic phosphodiesterase 4D is an enzyme that in humans is encoded by the PDE4D gene.
Receptor for activated C kinase 1 (RACK1), also known as guanine nucleotide-binding protein subunit beta-2-like 1 (GNB2L1), is a 35 kDa protein that in humans is encoded by the RACK1 gene.
cAMP-specific 3',5'-cyclic phosphodiesterase 4A is an enzyme that in humans is encoded by the PDE4A gene.
Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A is an enzyme that in humans is encoded by the PDE11A gene.
Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1A is an enzyme that in humans is encoded by the PDE1A gene.
High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A is an enzyme that in humans is encoded by the PDE7A gene. Mammals possess 21 cyclic nucleotide phosphodiesterase (PDE) genes that are pharmacologically grouped into 11 families. PDE7A is one of two genes in the PDE7 family, the other being PDE7B. The PDE7 family, along with the PDE4 and PDE8 families, are cAMP-specific, showing little to no activity against 3', 5'-cyclic guanosine monophosphate (cGMP).
cAMP-specific 3',5'-cyclic phosphodiesterase 4C is an enzyme that in humans is encoded by the PDE4C gene.
cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A is an enzyme that in humans is encoded by the PDE10A gene.
High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B is an enzyme that in humans is encoded by the PDE8B gene.
2′,3′-Cyclic-nucleotide 3'-phosphodiesterase is an enzyme that in humans is encoded by the CNP gene.
A phosphodiesterase-4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.
Piclamilast, is a selective PDE4 inhibitor. It is comparable to other PDE4 inhibitors for its anti-inflammatory effects. It has been investigated for its applications to the treatment of conditions such as chronic obstructive pulmonary disease, bronchopulmonary dysplasia and asthma. It is a second generation compound that exhibits structural functionalities of the PDE4 inhibitors cilomilast and roflumilast. The structure for piclamilast was first elucidated in a 1995 European patent application. The earliest mention of the name "piclamilast" was used in a 1997 publication.
3′,5′-cyclic-AMP phosphodiesterase (EC 3.1.4.53, cAMP-specific phosphodiesterase, cAMP-specific PDE, PDE1, PDE2A, PDE2B, PDE4, PDE7, PDE8, PDEB1, PDEB2) is an enzyme with systematic name 3′,5′-cyclic-AMP 5′-nucleotidohydrolase. It catalyses the following reaction
Cyclic di-AMP is a second messenger used in signal transduction in bacteria and archaea. It is present in many Gram-positive bacteria, some Gram-negative species, and archaea of the phylum euryarchaeota.
