phosphodiesterase

Phosphodiesterase (PDE), an enzyme capable of catalyzing the hydrolysis of the 3' ring phosphate bond in cyclic nucleotides, plays a crucial role in biochemical research and acts as a vital regulator in signal transduction processes involving the second messenger molecules cAMP and cGMP. Distinguished by their specificity to cyclic nucleotides, PDEs are categorized into different types ranging from PDE1 to PDE11, presenting potential significance in the study and treatment of various diseases [1].

IBMX (Methylisobutylxanthine) is a broad-spectrum phosphodiesterase (PDE) inhibitor with inhibitory activity against PDE3, PDE4, and PDE5 (IC50=6.5/26.3/31.7 μM). IBMX enhances the intracellular cAMP level.

MR-L2 is a reversible and noncompetitive allosteric activator of long-isoform phosphodiesterase-4 (PDE4).

Bucladesine sodium (DC2797) is a cAMP analog with cell-permeable properties. Bucladesine sodium is also a cAMP-dependent protein kinase (PKA) activator and a phosphodiester (PDE) inhibitor. Bucladesine sodium has anti-inflammatory activity.

Theophylline (1,3-Dimethylxanthine) is a methyl xanthine derivative from tea with diuretic, smooth muscle relaxant, bronchial dilation, cardiac, and central nervous system stimulant activities. It inhibits the 3', 5'-cyclic nucleotide phosphodiesterase that degrades cyclic AMP, thus potentiating the actions of agents that act through adenylyl cyclases and cyclic AMP.

Vesnarinone (Arkin) (INN) is a mixed phosphodiesterase 3 inhibitor and ion-channel modifier that has modest, dose-dependent, positive inotropic activity, but minimal negative chronotropic activity. It also suppresses cell proliferation and induces apoptosis by inducing the expression of p21, an inhibitor of cyclin-dependent kinase activity in p53-mediated cell cycle arrest.

Deltarasin is a small molecular inhibitor of KRAS-PDEδ interaction with Kd of 38 nM for binding to purified PDEδ.

Pentoxifylline (PTX) modulates immunologic activity by stimulating cytokine production. Pentoxifylline is a methylxanthine derivative that inhibits phosphodiesterase and affects blood rheology. It also inhibits platelet aggregation and improves blood flow by increasing erythrocyte and leukocyte flexibility.

Vardenafil (Vivanza) is an oral therapy for the treatment of erectile dysfunction. It is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMPspecific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP.

Anagrelide (Xagrid) is a Platelet-reducing Agent. The mechanism of action of anagrelide is as a Phosphodiesterase 3 Inhibitor. The physiologic effect of anagrelide is by means of Decreased Platelet Production.

Vinpocetine (RGH-4405) is a selective inhibitor of cyclic GMP phosphodiesterase (PDE).

Cilostazol (OPC 21) is a Phosphodiesterase 3 Inhibitor. The mechanism of action of cilostazol is as a Phosphodiesterase 3 Inhibitor.

Sildenafil citrate (UK-92480 citrate) , a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) Inhibitor, is used extensively for erectile dysfunction and less commonly for pulmonary hypertension.

Doxofylline (Doxophylline) is a methylxanthine derivative with the presence of a dioxolane group in position 7. As a drug used in the treatment of asthma, doxofylline has shown similar efficacy to theophylline but with significantly fewer side effects in animal and human studies.

Flavoxate hydrochloride (DW61) , a muscarinic AChR antagonist, is used in the therapy of various urinary syndromes and as an antispasmodic.

Diphylline (Diprophylline) is a xanthine derivative. Diphylline exerts bronchodilator effects and to a lesser extent vasodilator and diuretic properties. Diphylline probably acts as a competitive inhibitor of phosphodiesterase which leads to an increase in intracellular cAMP. This results in relaxation of bronchial smooth muscle and other smooth muscles. Diphylline may also antagonize adenosinereceptors. Diphylline is used in the treatment of acute bronchial asthma, chronic bronchitis and emphysema.

Roflumilast (APTA 2217) is an orally available, long-acting inhibitor of phosphodiesterase (PDE) type 4 (PDE4), with anti-inflammatory and potential antineoplastic activities. Upon administration, roflumilast and its active metabolite roflumilast N-oxide selectively and competitively bind to and inhibit PDE4, which leads to an increase of both intracellular levels of cyclic-3', 5'-adenosine monophosphate (cAMP) and cAMP-mediated signaling.

Milrinone (Win 47203) is a Phosphodiesterase 3 Inhibitor. The mechanism of action of milrinone is as a Phosphodiesterase 3 Inhibitor.

N-Methylbenzamide is a potent inhibitor of phosphodiesterase 10A (PDE10A) with demonstrated anti-cancer activity.

Amrinone (Inocor) is a positive inotropic cardiotonic (cardiotonic agent) with vasodilator properties, phosphodiesterase 3 inhibitory activity.

Tadalafil (IC-351) is a carboline-based compound with vasodilatory activity that selectively inhibits the cyclic guanosine monophosphate (cGMP)-specific type 5 phosphodiesterase (PDE-5), preventing cGMP degradation in the smooth muscle of the corpus cavernosa and corpus spongiosum of the penis, thereby causing prolonged muscle relaxation, vasodilation, and enhanced penile erection.

Dipyridamole (Persantin) is a Platelet Aggregation Inhibitor. The physiologic effect of dipyridamole is by means of Decreased Platelet Aggregation.

Aminophylline (Phyllocontin) is a competitive nonselective phosphodiesterase inhibitor giving a bronchodilatory effect.

Ibudilast (MN-166)(KC-404;AV-411;MN-166) is a relatively nonselective phosphodiesterase inhibitor. It is approved for use as an anti-inflammatory in Japan.