Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MK-886, a leukotriene biosynthesis inhibitor, which prevents the translocation and activation of 5-lipoxygenase, has been proposed as an effective drug for the treatment of inflammatory disorders, including psoriasis. In the present study, we investigated the effects of MK-886 on calmodulin as a potential target protein of anti-inflammatory drug activity, and on the proliferation of cultured human keratinocytes, a calmodulin-dependent cellular response with indicative value for antipsoriatic drug activity. Despite potent calmodulin-antagonistic activity in vitro, MK-886 failed to block cell proliferation in a human keratinocyte line, whereas trifluoperazine, a well characterized calmodulin antagonist with similar effects on calmodulin activity in our in vitro assays, inhibited cell proliferation in a dose-dependent manner. Further investigations on the mechanism of action revealed that, in contrast with trifluoperazine, calmodulin antagonism by MK-886 in vitro is likely to be mediated at the level of the allosteric calmodulin-recognition site of phosphodiesterase, rather than by binding to calmodulin itself. Therefore, our data do not conflict with the proposed role of calmodulin in the regulation of cell proliferation, but demonstrate that drug-induced antagonism of calmodulin, detected by inhibition of calmodulin-dependent enzymes in vitro, is not necessarily linked to antiproliferative activity in human keratinocytes.
...
PMID:Potent antagonism of calmodulin activity in vitro, but lack of antiproliferative effects on keratinocytes by the novel leukotriene biosynthesis inhibitor MK-886. 766 39

The cutaneous lymphocyte-associated antigen defines T lymphocytes with cutaneous tropism under inflammatory conditions. Bacterial infections participate in cutaneous inflammations, such as atopic dermatitis or psoriasis. Bacterial superantigens, such as staphylococcal enterotoxin B, can activate peripheral blood mononuclear cells to induce effector T cells bearing the T cell skin homing receptor cutaneous lymphocyte-associated antigen via enhancement of interleukin-12 production. We have identified and characterized the anti-inflammatory effects of different phosphodiesterase inhibitors on this system. Our data indicate that the selective type 4 phosphodiesterase inhibitor rolipram inhibits the Staphylococcal enterotoxin B-mediated generation of cutaneous lymphocyte-associated antigen positive CD3+ cells from peripheral blood mononuclear cells by reducing interleukin-12 production in a concentration-dependent manner. Conversely, type 3 phosphodiesterase or type 5 phosphodiesterase selective inhibitors were not effective. The rolipram inhibitory effect was on interleukin-12 production, as exogenously added interleukin-12 could revert rolipram suppression. These results suggest that selective type 4 phosphodiesterase inhibition may have beneficial effects on T cell mediated skin inflammatory processes characterized by the presence of bacterial infections, that are thought to exacerbate ongoing skin inflammation.
...
PMID:Rolipram inhibits staphylococcal enterotoxin B-mediated induction of the human skin-homing receptor on T lymphocytes. 1041 23

Psoriasis is an inflammatory disorder characterized by a T helper type 1 cell cytokine pattern. Increased expression of adhesion molecules, prominent neutrophil accumulation, and increased production of nitric oxide are characteristics of this disorder. Moreover, histamine and proteases are supposed to participate in the pathogenesis of psoriasis. Nicotinamide is an inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1) that, through enhancement of nuclear kappa B-mediated transcription, plays a pivotal role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Through interaction with CD38 and inhibition of IL-1, IL-12, and TNF-alpha production, nicotinamide produces a mild TH2 bias. Nicotinamide is a potent phosphodiesterase inhibitor and suppresses neutrophil chemotaxis and mast cell histamine release. It inhibits nitric oxide synthase mRNA induction and suppresses antigen-induced lymphocyte transformation. Nicotinamide increases the biosynthesis of ceramides, which upon degradation produce sphingosine. Sphingosine inhibits protein kinase C (PKC) and decreases basal cell proliferation dependent on PKC. Taken together, it can be reasoned that nicotinamide could be a useful addition to anti-psoriatic armamentarium. The combination of nicotinamide and thalidomide or methotrexate provided a powerful synergistic inhibition of murine collagen-induced arthritis. Nicotinamide decreased the methotrexate-induced hepatotoxicity. The above combinations may prove to have a powerful anti-psoriatic effect as well. As PARP inhibitors could exert anti-retroviral effect, nicotinamide could also be of special value in the treatment of HIV-infected psoriatics.
...
PMID:Nicotinamide: a potential addition to the anti-psoriatic weaponry. 1289 Jun 90

Roflumilast [APTA 2217, B9302-107, BY 217, BYK 20869] is a selective phosphodiesterase IV inhibitor. It is being developed by Altana Pharma (formerly Byk Gulden), a subsidiary of Altana Group, as an orally administered therapy for asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis and psoriasis. The drug is awaiting regulatory approval in Europe for the treatment of asthma and COPD. Byk Gulden has stated that roflumilast relieves asthma symptoms through both an anti-inflammatory effect and a muscle relaxant effect. Roflumilast has potential as first-line long-term therapy in mild-to-moderate COPD and as additive long-term therapy in moderate-to-severe COPD. Altana has stated that roflumilast is to be marketed under the brand name Daxas. Altana Group and Pharmacia Corporation (now Pfizer) signed an agreement on 22 April 2002 to collaborate on the development and commercialisation of roflumilast for the treatment of respiratory disorders, including asthma and COPD. The companies will jointly develop the drug for the US, Europe and other markets. Pharmacia will co-ordinate development in the US and Altana will co-ordinate development in Europe. After approval of the drug, Pharmacia and Altana will jointly launch and promote roflumilast in the US, Europe and elsewhere. Altana will receive an upfront payment and additional milestone payments. Altana additionally has the option to co-promote Pharmacia products in the US and elsewhere. On 16 April 2003, Pharmacia Corporation was acquired by, and merged into, Pfizer. In November 2002, Altana and Tanabe Seiyaku signed an agreement to collaborate on the development and commercialisation of roflumilast for the treatment of respiratory diseases, including asthma and COPD. Tanabe Seiyaku and Altana will develop roflumilast for asthma and COPD in Japan, and will jointly launch and co-promote roflumilast in Japan following regulatory approval. Roflumilast has been in multinational phase III clinical studies in Europe for the treatment of asthma and COPD. In September 2003, Altana announced the completion of a phase III trial in COPD in more than 1400 patients; the trial showed positive results. In the US, roflumilast is in phase III trials for the treatment of asthma and phase II trials for the treatment of COPD. Phase I clinical trials of roflumilast were begun in Japan by Tanabe Seiyaku in the fourth quarter of 2003. Altana has stated that roflumilast has shown significant superiority over placebo in the treatment of asthma in phase II trials. The efficacy of the drug appears to be comparable to low-dose inhaled corticosteroids in the treatment of asthma and at least equal to inhaled corticosteroids in the treatment of COPD. Altana Group presented data from phase II trials in 516 patients with COPD at an analyst meeting [August 2001, Bad Homburg, Germany] that showed that roflumilast 500 microg/day significantly improved FEV(1) at 24 weeks compared with placebo. In March 2004, Altana Pharma presented pharmacokinetic data from a phase I trial of roflumilast at the 60th Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI-2004) [San Francisco, CA, USA]. This open-label, randomised, two-period crossover study investigated the pharmacokinetics of oral roflumilast and its active metabolite, roflumilast N-oxide, among 12 healthy male subjects. Participants received single doses of oral roflumilast 500 microg and intravenous (i.v) roflumilast 150 microg as a 15-min short-term infusion. In November 2002, the combined global market for asthma and COPD products was estimated to be worth >11 billion US dollars. In Japan, products in this market segment reached sales of approximately 1.5 billion US dollars in 2001. Roflumilast has patent protection in Europe and Japan until 2014 and in the US until 2015. The Financial Times in April 2002 claimed that roflumilast is an 'important' product for Altana, due to be listed on the New York Stock Exchange later in the same month. The Altana chairman confirmed that the company had been in talks with Pfizer, Bristol-Myers Squibb and Novartis with regard to future development and commercialisation of roflumilast. In September 2002, Dow Jones Newswires stated that Altana is to file for European approval of roflumilast 1 year later than initially was expected; however, this has not changed the company's outlook for the product, which was said to remain at at 1 billion Euros. In August 2001, the Financial Times reported that roflumilast, for the indication of smoker's cough alone, has the potential to reach sales of more than 500 million US dollars a year. A future co-marketing deal for roflumilast in the US was said to be "a key step towards expanding Altana's presence in the US".
...
PMID:Roflumilast: APTA 2217, B9302-107, BY 217, BYK 20869. 1513 82

CC-10004, a phosphodiesterase 4 inhibitor and selective cytokine inhibitor, is under development by Celgene for the potential treatment of asthma, chronic obstructive pulmonary disease, inflammation and psoriasis. By October 2004, phase II trials in psoriasis had commenced.
...
PMID:CC-10004 . 1591 67

Cyclic AMP (cAMP) is a key second messenger in all cells. It is compartmentalized within cells and its levels are controlled, as a result of spatially discrete signaling cassettes controlling its generation, detection and degradation. Underpinning compartmentalized cAMP signaling are approximately 20 members of the phosphodiesterase-4 (PDE4) family. The selective inhibition of this family generates profound, functional effects and PDE4 inhibitors are currently under development to provide potential, novel therapeutics for the treatment of inflammatory diseases, such as asthma, chronic obstructive pulmonary disease and psoriasis, as well as treating depression and serving as cognitive enhancers. Here, we delineate the range of PDE4 isoforms, their role in signaling, their structural biology and related preclinical and clinical pharmacology.
...
PMID:Keynote review: phosphodiesterase-4 as a therapeutic target. 1625 73

Over the last fifteen years there has been much excitement in the idea that targeting phosphodiesterase (PDE) 4 with small molecule inhibitors could lead to the discovery of novel, steroid-sparing compounds with utility in treating a multitude of diseases associated with chronic inflammation. However, dose-limiting side effects, of which nausea and vomiting are the most common are worrisome, have hampered their clinical development. Indeed, a fundamental obstacle that still is to be overcome by the pharmaceutical industry is to make compounds that dissociate beneficial from the adverse events. Unfortunately, both of these activities of PDE4 inhibitors represents an extension of their pharmacology and improving the therapeutic ratio has proved to be a major challenge. Several strategies have been considered, with some degree of success, but compounds with an optimal pharmacophore still have not been reported. An alternative approach to targeting PDE4 is to inhibit other cAMP PDE families that are also expressed in immune and pro-inflammatory cells in the hope that the beneficial activity can be retained at the expense of side effects. One such candidate is PDE7A. In this article we review the literature on PDE7A and explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases including asthma, chronic obstructive pulmonary disease, atopic dermatitis, psoriasis, lupus, rheumatoid arthritis and multiple sclerosis.
...
PMID:Phosphodiesterase 7A: a new therapeutic target for alleviating chronic inflammation? 1702 May 29

The phosphodiesterase (PDE) 4 is the predominant cyclic AMP degrading enzyme in a variety of inflammatory cells including eosinophils, neutrophils, macrophages, T cells and monocytes. In addition, this enzyme is expressed in non-immune cells such as keratinocytes and fibroblasts. Highly selective PDE4 inhibitors are currently under evaluation for the treatment of asthma and/or chronic obstructive pulmonary disease. Due to the broad anti-inflammatory/immuno-modulatory action of PDE4 inhibitors, it has been proposed that PDE4 inhibitors might also be efficacious for skin disorders such as atopic dermatitis. Consequently, PDE4 inhibitors including cilomilast and AWD 12-281 have been tested in several models of allergic and irritant skin inflammation. These PDE4 inhibitors displayed strong anti-inflammatory action in models of allergic contact dermatitis in mice, in the arachidonic acid induced skin inflammation in mice and in ovalbumin sensitised guinea pigs. The determination of cytokines in skin homogenates revealed that both Th1 as well as Th2 cytokines are suppressed by PDE4 inhibitors, indicating an anti-inflammatory activity in both the Th2 dominated acute phase as well as the Th1 dominated chronic phase of atopic dermatitis. Due to the suppression of Th1 cytokines, activity can also be expected in psoriasis. Results of early clinical trials with both topically (cipamfylline, CP80,633) and systemically (CC-10004) active PDE4 inhibitors demonstrated efficacy in atopic dermatitis and in the case of CC-10004, also in psoriasis. AWD 12-281 (GW 842470) is currently under clinical evaluation for the topical treatment of atopic dermatitis. Results concerning clinical efficacy of this potent and selective PDE4 inhibitor are anxiously awaited.
...
PMID:Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. 1735 85

Trypanosoma cruzi phosphodiesterase (PDE) C (TcrPDEC), a novel and rather unusual PDE in which, unlike all other class I PDEs, the catalytic domain is localized in the middle of the polypeptide chain, is able to hydrolyze cyclic GMP (cGMP), although it prefers cyclic AMP (cAMP), and has a FYVE-type domain in its N-terminal region (S. Kunz et al., FEBS J. 272:6412-6422, 2005). TcrPDEC shows homology to the mammalian PDE4 family members. PDE4 inhibitors are currently under development for the treatment of inflammatory diseases, such as asthma, chronic pulmonary diseases, and psoriasis, and for treating depression and serving as cognitive enhancers. We therefore tested a number of compounds originally synthesized as potential PDE4 inhibitors on T. cruzi amastigote growth, and we obtained several useful hits. We then conducted homology modeling of T. cruzi PDEC and identified other compounds as potential inhibitors through virtual screening. Testing of these compounds against amastigote growth and recombinant TcrPDEC activity resulted in several potent inhibitors. The most-potent inhibitors were found to increase the cellular concentration of cAMP. Preincubation of cells in the presence of one of these compounds stimulated volume recovery after hyposmotic stress, in agreement with their TcrPDEC inhibitory activity in vitro, providing chemical validation of this target. The compounds found could be useful tools in the study of osmoregulation in T. cruzi. In addition, their further optimization could result in the development of new drugs against Chagas' disease and other trypanosomiases.
...
PMID:Chemical validation of phosphodiesterase C as a chemotherapeutic target in Trypanosoma cruzi, the etiological agent of Chagas' disease. 2062 48

Since more than two decades anti-inflammatory effects of inhibitors of phosphodiesterase-4 have been described in numerous cellular and animal studies and were finally confirmed in clinical trials. The path from an early, pioneering study with Ro20-1724 showing reduction of psoriatric plaque size in 1979 to modern PDE4 inhibitors such as oral apremilast in development for psoriasis, the inhaled PDE4 inhibitor GSK256066 in development for asthma and COPD and finally roflumilast, the first PDE4 inhibitor approved and currently marketed as an oral, once-daily remedy for severe COPD was marked by large progress in chemical optimization based on improved understanding of PDE4 biology and drug-like properties determining the appropriate pharmacokinetic profile. In this chapter aspects of the pharmacology and clinical efficacy of PDE4 inhibitors, which have been in clinical development over the years are summarized with specific emphasis on their clinical pharmacokinetic properties.
...
PMID:Pharmacology, clinical efficacy, and tolerability of phosphodiesterase-4 inhibitors: impact of human pharmacokinetics. 2169 36


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---