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

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

By the reaction of 2-chloro-5-(4-pyridinyl)pyridines 1-6 with morpholine as well as by derivation of the 2-morpholino-pyridine-3-carboxamide 8 the 3-substituted 2-morpholino-5-(4-pyridinyl)pyridines 7-14 were prepared. The evaluation for positive inotropic properties in spontaneously beating isolated guinea pig atria gave for the 3-cyano derivative 7 (AWD 122-14) the best activity. The potency is comparable to that of milrinone and is due to partial by inhibition of phosphodiesterase III (PDE III).
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PMID:[Potential cardiotonics. 14. Synthesis and in vitro positive inotropic actions of 4-morpholino-5-(4-pyridinyl)pyridine derivatives]. 148 Jun 54

The presence of a nucleotide pyrophosphatase (EC 3.6.1.9) on the plasma membrane of rat C6 glioma has been demonstrated by analysis of the hydrolysis of ATP labeled in the base and in the alpha- and gamma-phosphates. The enzyme degraded ATP into AMP and PPi and, depending on the ATP concentration, accounted for approximately 50-75% of the extracellular degradation of ATP. The association of the enzyme with the plasma membrane was confirmed by ATP hydrolysis in the presence of a varying concentration of pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), a membrane-impermeable inhibitor of the enzyme. PPADS concentration above 20 microM abolished the degradation of ATP into AMP and PPi. The nucleotide pyrophosphatase has an alkaline pH optimum and a Km for ATP of 17 +/- 5 microM. The enzyme has a broad substrate specificity and hydrolyzes nucleoside triphosphates, nucleoside diphosphates, dinucleoside polyphosphates, and nucleoside monophosphate esters but is inhibited by nucleoside monophosphates, adenosine 3',5'-bisphosphate, and PPADS. The substrate specificity characterizes the enzyme as a nucleotide pyrophosphatase/phosphodiesterase I (PD-I). Immunoblotting and autoadenylylation identified the enzyme as a plasma cell differentiation antigen-related protein. Hydrolysis of ATP terminates the autophosphorylation of a nucleoside diphosphate kinase (NDPK/nm23) detected in the conditioned medium of C6 cultures. A function of the pyrophosphatase/PD-I and NDPK in the purinergic and pyrimidinergic signal transduction in C6 is discussed.
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PMID:An ecto-nucleotide pyrophosphatase is one of the main enzymes involved in the extracellular metabolism of ATP in rat C6 glioma. 993 Jul 59

Non-selective inhibitors of cyclic nucleotide phosphodiesterase (PDE) block allergen-induced contraction of passively sensitized human airways in vitro by a dual mechanism involving a direct relaxant effect on smooth muscle and inhibition of histamine and cysteinyl leukotriene (LT) release from airways. We investigated the effects of non-selective PDE inhibitors and selective inhibitors of PDE3 and PDE4 in order to determine the involvement of PDE isoenzymes in the suppression of allergic bronchoconstriction. Macroscopically normal airways from 76 patients were sensitized with IgE-rich sera (>250 u ml(-1)) containing specific antibodies against allergen (Dermatophagoides farinae). Contractile responses of bronchial rings were assessed using standard organ bath techniques. Passive sensitization caused increased contractile responses to allergen, histamine and LTC(4). Non-selective PDE inhibitors (theophylline, 3-isobutyl-1-methylxanthine [IBMX]), a PDE3-selective inhibitor (motapizone), PDE4-selective inhibitors (RP73401, rolipram, AWD 12-281) and a mixed PDE3/4 inhibitor (zardaverine) all significantly relaxed inherent bronchial tone at resting tension and to a similar degree. Theophylline, IBMX, zardaverine and the combination of motapizone and RP73401 inhibited the contractile responses to allergen and LTC(4). Pre-treatment with motapizone, RP73401, rolipram or the methylxanthine adenosine receptor antagonist, 8-phenyltheophylline, did not significantly decrease responses to either allergen or LTC(4). We conclude that combined inhibition of PDE3 and PDE4, but not selective inhibition of either isoenzyme or antagonism of adenosine receptors, is effective in suppressing allergen-induced contractions of passively sensitized human airways. The relationship between allergen- and LTC(4)-induced responses suggests that PDE inhibitors with PDE3 and PDE4 selectivity are likely to act in part through inhibition of mediator release and not simply through direct relaxant actions on airway smooth muscle.
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PMID:The effect of selective and non-selective phosphodiesterase inhibitors on allergen- and leukotriene C(4)-induced contractions in passively sensitized human airways. 1113 38

Human eosinophils contain predominantly phosphodiesterase type IV, but selective inhibitors of this isoenzyme fail to inhibit certain eosinophil responses such as degranulation. In this study, the effect of activation of adenylate cyclase on the ability of several highly selective PDE IV inhibitors to inhibit complement C5a-induced O2- release and degranulation of human eosinophils in vitro was investigated. All four selective PDE IV inhibitors, N-(3,5-dichloropyrid-4-yl)-3-cyclopentyl-oxy-4-methoxybenzamide (RP 73401), rolipram, N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3-yl]glyoxylacidamide (AWD 12-281) and c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl-r-1-cyclohexane carboxylic acid) (SB 207499) potently inhibited C5a-induced O2- generation (IC50 = 0.03, 0.42, 0.55 and 0.86 microM, respectively), but generally failed to inhibit degranulation. The only exception was AWD 12-281, which inhibited degranulation (IC50 = 16.2 microM). In the presence of different AC activators (histamine, salbutamol, prostaglandin E2 and forskolin), the PDE IV inhibitors became potent inhibitors of degranulation. The interaction between the PDE IV inhibitors and the AC activators resulted in a synergistic increase in intracellular levels of adenosine 3', 5'-monophosphate (cAMP). These results show that PDE IV inhibitors generally require an additional cAMP signal to be able to inhibit eosinophil degranulation, and that this signal can be generated via both membrane receptors and direct AC activation. This may be relevant to the in vivo effectiveness of PDE IV inhibitors in eosinophilic inflammation.
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PMID:Requirement of additional adenylate cyclase activation for the inhibition of human eosinophil degranulation by phosphodiesterase IV inhibitors. 1130 Oct 54

The inhibitors of the phosphodiesterase 4, SB 207499 (cilomilast, c-4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-r-L-cyclohexane carboxylic acid) and AWD 12-281 (N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide) were tested in a model of allergic dermatitis in mice. To obtain an allergic dermatitis, BALB/c mice were sensitized to toluene-2,4-diisocyanate. The allergic reaction was challenged by topical administration of toluene-2,4-diisocyanate onto the mice ears. Before challenge, two groups of mice were treated topically (ear skin) with SB 207499 or AWD 12-281. There was a significant ear swelling in toluene-2,4-diisocyanate-challenged mice ears 4, 8, 16, 24 and 48 h after challenge. SB 207499 and AWD 12-281 inhibited this swelling significantly 8, 16, 24 and 48 h after the challenge. For biochemical parameters and histology, ears were sampled from mice sacrificed 4, 8 and 16 h after the challenge. In homogenized tissue, SB 207499 and AWD 12-281 inhibited significantly the secretion of interleukin 1beta induced by toluene-2,4-diisocyanate 4 and 8 h after challenge. The cell influx (granulocytes) observed in the toluene-2,4-diisocyanate-challenged mice 8 and 16 h after challenge was nearly abolished by AWD 12-281 and SB 204799.
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PMID:Effects of the phosphodiesterase 4 inhibitors SB 207499 and AWD 12-281 on the inflammatory reaction in a model of allergic dermatitis. 1209 2

N-(3,5-Dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281) is a highly potent and selective phosphodiesterase 4 (PDE4) inhibitor that was designed to have a metabolic profile that was optimized for topical administration. The aim of the current study was to explore the pharmacological profile of intratracheally administered AWD 12-281 in different models of asthma and chronic obstructive pulmonary disease (COPD) in comparison with steroids. To assess the anti-inflammatory potential of AWD 12-281, the antigen-induced cell infiltration in bronchoalveolar lavage fluid (BALF) of Brown Norway rats was determined. AWD 12-281 (ID50 of 7 microg/kg i.t.) as well as beclomethasone (0.1microg/kg i.t.) suppresses late-phase eosinophilia when administered intrapulmonary. Furthermore, AWD 12-281 has also strong anti-inflammatory properties when tested in lipopolysaccharide-induced acute lung neutrophilia in Lewis rats (ID50 of 0.02 microg/kg i.t.), ferrets (ID50 of 10 microg/kg i.t.), and domestic pigs (2-4 mg/pig i.t. or 1 mg/kg i.v.). In pigs, AWD 12-281 was as effective as beclomethasone (0.4 mg/pig i.t.) and dexamethasone (0.28 mg/kg i.v.), although at 3 to 10 times the dosage. The bronchodilatory activity of AWD 12-281 was assessed in sensitized guinea pigs. AWD 12-281 (1.5 mg/kg i.t., 1-h pretreatment) inhibited allergen-induced bronchoconstriction by 68% (parameter airway resistance). In sensitized BP-2 mice AWD 12-281 abolished the allergen-induced bronchial hyperresponsiveness and eosinophilia in BALF, showing dose dependence. When given orally, i.v. or i.t., AWD 12-281 has a considerably lower emetic potential than cilomilast in ferrets and roflumilast in pigs. When given topically by inhalation, no emesis could be induced in dogs up to the highest feasible dose (15 mg/kg in 50% lactose blend). These results indicate that AWD 12-281 is a unique potential new drug for the topical treatment of asthma and COPD.
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PMID:In vivo efficacy in airway disease models of N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281), a selective phosphodiesterase 4 inhibitor for inhaled administration. 1294 97

AWD 12-281 (N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide), a phosphodiesterase 4 inhibitor, which is optimized for topical administration, was tested in a model of allergic dermatitis in mice. To obtain an allergic dermatitis, BALB/c mice were sensitized to toluene-2,4-diisocyanate (TDI). The allergic reaction was challenged by topical administration of TDI onto the mice ears. AWD 12-281 was tested for its anti-inflammatory potential by oral, intraperitoneal and topical administration. The phosphodiesterase 4 inhibitor, cilomilast (SB 207499), and/or the corticosteroid, diflorasone diacetate, were used as reference compounds. Given orally and intraperitoneally 2 h before as well as 5 and 24 h after TDI challenge, AWD 12-281 showed no, or only a transient inhibition of the allergen-induced ear swelling, whereas cilomilast significantly inhibited this ear swelling. Applied topically onto the ears before TDI challenge, AWD 12-281, cilomilast and diflorasone diacetate caused total inhibition of ear swelling 24 h after challenge, confirmed by a decrease of the pro-inflammatory cytokines interleukin-4, interleukin-6 and macrophage inhibitory protein-2. Administered topically after TDI challenge as therapeutic intervention, AWD 12-281 and diflorasone diacetate caused significant inhibition of ear swelling; cilomilast failed to do so. These results indicate that topically administered AWD 12-281 may be potent in the prevention and treatment of allergic/inflammatory skin diseases.
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PMID:AWD 12-281, a highly selective phosphodiesterase 4 inhibitor, is effective in the prevention and treatment of inflammatory reactions in a model of allergic dermatitis. 1295

Cyclic adenosine monophosphate (cAMP) is thought to be associated with inflammatory cell activity: high levels tend to decrease proliferation and cytokine secretion, whereas low concentrations have the opposite effect (1). Since many phosphodiesterases (PDEs) degrade cAMP, inhibitors of this enzyme decrease inflammatory cell activity. Theophylline, which has nonselective PDE inhibitor activity in addition to its other mechanisms of action, has been used in the treatment of asthma for many years. Unfortunately, because of the important role of PDEs in the cell, nonspecific inhibition of these enzymes causes many undesirable side effects. The discovery of PDE isoenzyme families (PDE1-PDE10), their subtypes (HPDE4 and LPDE4) and their differential distribution among the cell types, as well as their specific functions in controlling cell processes, has led to the development of new, specific PDE4 inhibitors. This review details the rationale for the use of PDE4 inhibitors in the treatment of allergic disease. In addition, the effects of PDE4 inhibitors in vitro, in preclinical animal models and in the clinic are covered. Finally, up-to-date information on the most recently developed inhibitors, such as SB-207499, CDP-840, AWD-12-281 and D-4418, is provided.
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PMID:Therapeutic potential of phosphodiesterase 4 inhibitors in allergic diseases. 1297 97

Escherichia coli nucleoside diphosphate kinase (eNDK) is an XTP:XDP phosphotransferase that plays an important role in the regulation of cellular nucleoside triphosphate concentrations. It is also one of several recently discovered DNases belonging to the NM23/NDK family. E. coli cells disrupted in the ndk gene display a spontaneous mutator phenotype, which has been attributed to the mutagenic effects of imbalanced nucleotide pools and errors made by replicative DNA polymerases. Another explanation for the increased mutation rates is that endk- cells lack the nuclease activity of the NDK protein that is essential for a DNA repair pathway. Here, we show that purified, cloned endk is a DNA repair nuclease whose substrate is uracil misincorporated into DNA. We have identified three new catalytic activities in eNDK that act sequentially to repair the uracil lesion: (i) uracil-DNA glycosylase that excises uracil from single-stranded and from U/A and U/G mispairs in double-stranded DNA; (ii) apyrimidinic endonuclease that cleaves double-stranded DNA as a lyase by forming a covalent enzyme-DNA intermediate complex with the apyrimidinic site created by the glycosylase; and (iii) DNA repair phosphodiesterase that removes 3'-blocking residues from the ends of duplex DNA. All three of these activities, as well as the nucleoside-diphosphate kinase, reside in the same protein. Based on these findings, we propose an editing function for eNDK as a mechanism by which the enzyme prevents mutations in DNA.
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PMID:Escherichia coli nucleoside diphosphate kinase is a uracil-processing DNA repair nuclease. 1458 34

AWD 12-281 is a potent (IC(50) = 9.7 nM) and highly selective inhibitor of the phosphodiesterase 4 (PDE4) isoenzyme with low affinity to the high-affinity rolipram-binding site. The compound was optimized for topical treatment of asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis. The aim of the present study was to assess the effect of AWD 12-281 in human inflammatory cells. Peripheral blood mononuclear cells (PBMCs), diluted whole blood, and human nasal polyp cells derived from surgically resected nasal polyps from patients with polyposis comprise sources of target tissue cells that can be used to predict anti-inflammatory effects in patients. AWD 12-281 was capable of suppressing the production of cytokines in stimulated PBMCs: interleukin-2 (IL-2, phytohemagglutinin stimulation), IL-5 (concanavalin A stimulation), IL-5 and IL-4 (anti-CD3/anti-CD28 costimulation), and lipopolysaccharide-stimulated release of tumor necrosis factor alpha (TNF alpha). The corresponding values for half-maximum inhibition, EC(50), for AWD 12-281 were within a narrow range (46-121 nM). Comparing the effect of AWD 12-281 with roflumilast, cilomilast (SB 207499), rolipram (RPR-73401), and 1-(3-nitrophenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidin-2,4(1H,3H)-dione (RS-25344-000), it could be shown that the PDE4 inhibitory activity was closely correlated with inhibitory potential as measured by the above-described assays. AWD 12-281 was also shown to suppress TNF alpha release in dispersed nasal polyps (EC(50) = 111 nM) and in diluted whole blood (EC(50) = 934 nM). The reduced activity in human blood may be related to high plasma protein binding. Currently, phase II clinical studies are under way to evaluate the therapeutic potential of AWD 12-281 in asthma, COPD, and allergic rhinitis.
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PMID:Anti-inflammatory potential of the selective phosphodiesterase 4 inhibitor N-(3,5-dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281), in human cell preparations. 1461 Feb 30


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