Apremilast (brand name Otezla) selective inhibitor of phosphodiesterase 4 is used for the treatment of patients with moderate to severe plaque psoriasis. OTEZLA is the first and only PDE4 inhibitor approved for the treatment of plaque psoriasis, a chronic inflammatory disease of the skin resulting from an uncontrolled immune response. Apremilast also inhibits spontaneous production of TNF-alpha from human rheumatoid synovial cells. It has anti-inflammatory activity. By inhibiting PDE-4, apremilast increases intracellular levels of cAMP and thereby inhibits the production of multiple proinflammatory mediators including PDE-4, TNF-alpha, interleukin-2 (IL-2), interferon-gamma, leukotrienes, and nitric oxide synthase.

Roflumilast is a specific phosphodiesterase type (4PDE4) inhibitor indicated for use as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.

Dipyridamole, a non-nitrate coronary vasodilator that also inhibits platelet aggregation, is combined with other anticoagulant drugs, such as warfarin, to prevent thrombosis in patients with valvular or vascular disorders. Dipyridamole is also used in myocardial perfusion imaging, as an antiplatelet agent, and in combination with aspirin for stroke prophylaxis. Dipyridamole likely inhibits both adenosine deaminase and phosphodiesterase, preventing the degradation of cAMP, an inhibitor of platelet function. This elevation in cAMP blocks the release of arachidonic acid from membrane phospholipids and reduces thromboxane A2 activity. Dipyridamole also directly stimulates the release of prostacyclin, which induces adenylate cyclase activity, thereby raising the intraplatelet concentration of cAMP and further inhibiting platelet aggregation. Used for as an adjunct to coumarin anticoagulants in the prevention of postoperative thromboembolic complications of cardiac valve replacement and also used in prevention of angina.

Since its discovery as component of the tea leaf by Albert Kossel in 1888, the history of theophylline (CAS 58-55-9) has been a long and successful one. At the turn of the century, theophylline became less expensive due to chemical synthesis and was primarily used as diuretic in subsequent years. It was Samuel Hirsch who discovered the bronchospasmolytic effect of theophylline in 1992, however, despite this pioneering discovery theophylline continued to be used primarily as diuretic and cardiac remedy. The molecular mechanism of bronchodilatation is inhibition of phosphodiesterase(PDE)3 and PDE4, but the anti-inflammatory effect may be due to histone deacetylase (HDAC) activation, resulting in switching off of activated inflammatory genes. Theophylline is indicated for the treatment of acute exacerbations of the symptoms and reversible airflow obstruction associated with asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

Exisulind (tentative trade name Aptosyn) is an antineoplastic agent, which was originally developed by Cell Pathways. This drug is an inhibitor of phosphodiesterase (PDE) isozymes: PDE5 and PDE4. Inhibition of PDE5 appears to be pharmacologically relevant, which leads to increase cGMP and activate protein kinase G at doses that induce apoptosis, whereas cyclic AMP levels were not changed. Exisulind has been in phase III clinical trials for the treatment of Non-Small Cell Lung Cancer and for the treatment of polyps in patients who have familial adenomatous polyposis (Colorectal Cancer and Small Intestine Cancer). In addition, this drug was in phase II/III for the treatment of Prostate Cancer, however, there studies have been discontinued.

Etazolate (EHT-0202) is a selective, positive GABAA receptor modulator has completed phase II clinical trials in patients with Alzheimer's disease. It is also a selective phosphodiesterase-4 inhibitor that is specific for cAMP. Etazolate showed anxiolytic and antidepressant activity and could be useful in managing post-traumatic stress disorder.

E-6005 is a novel PDE4 inhibitor developed as a topical agent for atopic dermatitis (AD). It potently and selectively inhibited human PDE4 activity and suppressed the production of various cytokines from human lymphocytes and monocytes. In mice models, the topical application of E6005 produced an immediate antipruritic effect as well as an anti-inflammatory effect with reduced expression of cytokines/adhesion molecules. E-6005 increases the cutaneous concentration of cAMP to relieve dermatitis-associated itching. E-6005 may be a promising novel therapeutic agent with antipruritic activity for the treatment of AD. E-6005 is currently in phase 2 development for patients with mild-to-moderate atopic dermatitis.

Inflazyme Pharmaceuticals initially developed HT-0712 as a phosphodiesterase IV (PDE4) inhibitor with anti-inflammatory properties. Now the rights on this drug are wholly owned by Dart NeuroScience. January 2015, Dart NeuroScience completed a phase II trial of HT-0712 for the memory disorders, where were evaluated the efficacy in improving memory and cognitive performance.

Trequinsin is a potent PDE3 inhibitor that inhibits PDE4 and PDE2 at higher concentrations. Trequinsin can block platelet aggregation and also inhibit tissue factor expression in human endothelial cells. Trequinsin can enhance cellular cAMP content, forskolin-induced cAMP synthesis, and renin release in cells.

Otsuka Pharmaceutical Co developed tetomilast, a thiazole derivative for the treatment of inflammatory bowel disease and chronic obstructive pulmonary disease. Tetomilast acts as a selective inhibitor of phosphodiesterase-4 results in increased intracellular levels of cyclic adenosine monophosphate (cAMP), and subsequent anti-inflammatory effects. Specifically, the release of pro-inflammatory mediators including TNF-a and IL-12 is suppressed, and there is stimulation of the release of anti-inflammatory mediators including IL-10 and prostaglandin E2. Unfortunately, tetomilast clinical trials in patients with ulcerative colitis failed to demonstrate superior efficacy compared to mesalamine and further development of tetomilast was discontinued.