GlaxoSmithKline is developing GSK-356278 as a selective, brain-penetrant phosphodiesterase 4 (PDE4) inhibitor that demonstrates anxiolytic and cognition-enhancing effects. Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. The drug was studied for the treatment of Huntington's disease, depressive and anxiety disorders. GSK-356278 has completed phase I clinical trials for evaluation of the safety, tolerability, and pharmacokinetics in male volunteers with the therapeutic dose for future clinical development.

Oglemilast (GRC-3886), is a potent and selective PDE4 inhibitor (IC50: 2.5 nM (PDE4B) and 1.7 nM (PDE4D)). Oglemilast is in phase II clinical trials for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Oglemilast was originally developed by Glenmark Pharmaceuticals, and licensed to Forest (acquired by Actavis in 2014) for the rights in North America in 2004. Teijin Pharma obtained the rights of the compound in Japan in 2005.

Piclamilast (RP 73401), 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 asthma, dermatitis, rheumatoid arthritis. Emesis is the most commonly cited side effect of piclamilast.

Atizoram (CP-80633) is a phosphodiesterase IV inhibitor with bronchodilatory and antiinflammatory properties. It was in phase II trials with Pfizer in the US for the treatment of asthma, atopic dermatitis and psoriasis. Development of atizoram has been discontinued in the asthma indication and no recent development has been reported for the other indications. CP-80633 inhibits PDE4 isozymes (human lung IC50 = 1.27 uM) in the absence of effects on PDE1, PDE2, PDE3 and PDE5 isozymes (IC50 > 100 uM). It exhibits no significant selectivity for any single cloned PDE4A, B, C or D isoform.

RS25344 is a potent and selective phosphodiesterase (PDE) 4 inhibitor. It preferentially inhibits phosphorylated PDE4D. The compound demonstrated efficacy in animal models of inflammation and anaphylaxis. RS25344 inhibited eosinophil chemotaxis, increased the progressive motility of bovine spermatozoa, inhibited leukotriene B4 biosynthesis by human polymorphonuclear leukocytes.

CDP 840 hydrochloride is a potent and selective inhibitor of phosphodiesterase 4 (PDE4). This compound competitively inhibits all PDE4 isoenzymes, which in turn prevents the cleavage of phosphodiester bonds found in secondary messenger molecules. CDP-840 had been in phase II clinical trials for the treatment of asthma. However, CDP840 did not lead to changes in baseline forced expiratory volume in one second (FEV1) as compared to placebo. CDP 840 research has been discontinued.

4LSC379 (D159687) is a small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity. It has reduced potential to cause emesis, while maintaining biological activity in cellular and in vivo models.

Zardaverine (6-(4-difluoromethoxy-3-methoxyphenyl)-3[2H]pyridazinone) is a dual-selective inhibitor of phosphodiesterase III/IV was developed as a potential therapeutic agent for asthma. Zardaverine has been shown to inhibit inflammatory cell function, human peripheral blood mononuclear cells (PBMC) and T-cell proliferation and exert a positive inotropic action on the heart muscle. In animals, zardaverine exhibits both bronchodilatory and anti-inflammatory activities. In order to study the efficacy and safety in man, Zardaverine has been tested in clinical trials for the treatment COPD and asthma. Zardaverine has a modest and short-lasting bronchodilatory effect in patients with asthma. However, due to its fast elimination, the development of zardaverine was terminated in 1991.

Cilomilast (Ariflo) is an oral selective phosphodiesterase (PDE) IV inhibitor under development by GlaxoSmithKline Pharmaceuticals for treatment of COPD. After the demise of Merck's PDE-IV inhibitor (licensed from Celltech Group) in April 2003, Ariflo has emerged as the frontrunner in this new class of agents for inflammatory airways diseases, such as COPD. GlaxoSmithKline filed for drug approval with the US FDA at the end of 2002 and in January 2003 with the European Medicines Evaluation Agency (EMEA). In October 2003 the FDA issued an approvable letter for use of Ariflo in maintenance of lung function in COPD patients poorly responsive to salbutamol, despite an earlier decision by the FDA advisory panel to reject approval. Cilomilast shows high selectivity for cAMP-specific PDE4, an isoenzyme that predominates in pro-inflammatory and immune cells and that is 10-fold more selective for PDE4D than for PDE4A, -B or -C. In vitro, cilomilastsuppresses the activity of several pro-inflammatory and immune cells that have been implicated in the pathogenesis of asthma and COPD. Moreover, it is highly active in animal models of these diseases. Cilomilast has been shown to exert potent anti-inflammatory effects both in vitro and in vivo.