Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, we reported structurally novel PDE4 inhibitors based on 1,4-benzodiazepine derivatives. The main interest in developing bezodiazepine-based PDE4 inhibitors is in their lack of adverse effects of emesis with respect to rolipram-like compounds. A large effort has thus been made toward the structural optimization of this series. In the absence of structural information on the inhibitor binding mode into the PDE4 active site, 2D-QSAR (H-QSAR) and two 3D-QSAR (CoMFA and CoMSIA) methods were applied to improve our understanding of the molecular mechanism controlling the PDE4 affinity of the benzodiazepine derivatives. As expected, the CoMSIA 3D contour maps have provided more information on the benzodiazepine interaction mode with the PDE4 active site whereas CoMFA has built the best tool for activity prediction. The 2D pharmacophoric model derived from CoMSIA fields is consistent with the crystal structure of the PDE4 active site reported recently. The combination of the 2D and 3D-QSAR models was used not only to predict new compounds from the structural optimization process, but also to screen a large library of bezodiazepine derivatives.
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PMID:CoMFA and CoMSIA 3D-quantitative structure-activity relationship model on benzodiazepine derivatives, inhibitors of phosphodiesterase IV. 1177 90

1. Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha(2)-adrenoceptor antagonists. This has been postulated as the mechanism by which PDE4 inhibitors induce emesis and was also demonstrated by their ability to reverse xylazine/ketamine-induced anaesthesia. We further characterized this latter effect since it appears to reflect the emetic potential of PDE4 inhibitors. 2. Selective inhibitors of PDE 1, 2, 3, 4 and 5 were studied in rats, on the duration of anaesthesia induced by the combination of xylazine (10 mg kg(-1), i.m.) and ketamine (10 mg kg(-1), i.m.). PMNPQ (i.e. 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline) - PDE4 inhibitor: 0.01 - 3 mg kg(-1)), like MK-912 (alpha(2)-adrenoceptor antagonist: 0.01 - 3 mg kg(-1)), dose-dependently reduced the duration of anaesthesia. In contrast, vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor), milrinone (PDE3 inhibitor) and zaprinast (PDE5 inhibitor) had no significant effect at the doses tested (1 - 10 mg kg(-1)). Analysis of plasma and cerebrospinal fluid (CSF) of treated animals confirmed the absorption and distribution to the brain of the inactive inhibitors. 3. Neither MK-912 (3 mg kg(-1)) nor PMNPQ (0.1 - 1 mg kg(-1)) altered the duration of anaesthesia induced via a non-alpha(2)-adrenoceptor pathway (sodium pentobarbitone 50 mg kg(-1), i.p.). 4. Central NK(1) receptors are involved in PDE4 inhibitor-induced emesis. Consistently, [sar(9), Met(O(2))(11)]-substance P (NK(1) receptor agonist, 6 microg i.c.v.) reduced the duration of anaesthesia induced by xylazine/ketamine. 5. In summary, this model is functionally coupled to PDE4, specific to alpha(2)-adrenoceptors and relevant to PDE4 inhibitor-induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats.
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PMID:Assessing the emetic potential of PDE4 inhibitors in rats. 1178 86

The phosphodiesterases (PDEs) are responsible for the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate (cAMP and cGMP, respectively). They are classified into 11 major families (PDE1-11) and the type 4 phosphodiesterase (PDE4) is a cAMP-specific enzyme localized in airway smooth muscle cells as well as in immune and inflammatory cells. The PDE4 activity is associated with a wide variety of diseases some of which have been related to an inflammatory state, (e.g. asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA)) while others have recently been connected to autoimmune pathology. Therefore, an intense effort toward the development of PDE4 inhibitors has been generated for the last decade. Unfortunately, the effects of prototype PDE4 inhibitors have been compromised by side effects such as nausea and emesis and the clinical use of those compounds is still limited. Several companies have focused on the design of a new generation of PDE4 inhibitors dissociating beneficial activity and adverse effects. This review highlights the recent data of the most advanced clinical candidates, the design and structure activity relationships of the recent structural series reported in the literature over the last two years, as well as recent advances in the multiple therapeutic indications of PDE4 inhibitors (a review with 375 references).
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PMID:Recent advances in PDE4 inhibitors as immunoregulators and anti-inflammatory drugs. 1205 19

N-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 351591) has been identified as a potent (IC(50) = 58 nM) and highly selective type 4 phosphodiesterase (PDE4) inhibitor with oral bioactivity in several animal models of lung inflammation. N-(3,5-Dichloro-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 365351), the only significant in vivo metabolite, is also a potent and highly selective PDE4 inhibitor (IC(50) = 20 nM). Both SCH 351591 and SCH 365351 inhibited cytokine production in human blood mononuclear cell preparations. Oral SCH 351591 significantly attenuated allergen-induced eosinophilia and airway hyperreactivity in allergic guinea pigs at doses as low as 1 mg/kg. In this model, oral SCH 365351 showed similar potency. When SCH 351591 was administered orally to allergic cynomolgus monkeys at 3 mg/kg, Ascaris suum-induced lung eosinophilia was blocked. Hyperventilation-induced bronchospasm in nonallergic guinea pigs, a model for exercise-induced asthma, was also suppressed significantly by oral SCH 351591 at 0.3 mg/kg. Cilomilast (SB 207499; Ariflo), a PDE4 inhibitor currently being developed for asthma and chronic obstructive pulmonary disease (COPD), was 10- to 30-fold less potent than SCH 351591 at inhibiting guinea pig lung eosinophilia and hyperventilation-induced bronchospasm. In a ferret model of emesis, maximum nonemetic oral doses of SCH 351591 and cilomilast were 5 and 1 mg/kg, respectively. Comparison of plasma levels at these nonemetic doses in ferrets to those at doses inhibiting hyperventilation-induced bronchospasm in guinea pigs gave a therapeutic ratio of 16 for SCH 351591 and 4 for cilomilast. Thus, SCH 351591 exhibits a promising preclinical profile as a treatment for asthma and COPD.
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PMID:Pharmacology of N-(3,5-dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 351591), a novel, orally active phosphodiesterase 4 inhibitor. 1206 9

cAMP plays an important role as a second-messenger molecule controlling multiple cellular processes. Its hydrolysis provides an important mechanism by which cAMP levels are regulated. This is performed by a large multigene family of cyclic nucleotide phosphodiesterases (PDEs). Members of the PDE4 enzyme family are selectively inhibited by rolipram. Five different mRNA splice forms for PDE4D have been isolated. Here, we analyzed the regional distribution of the mRNAs coding for the splice variants PDE4D1, PDE4D2, PDE4D3, PDE4D4, and PDE4D5 in the rat brain by in situ hybridization histochemistry using specific radiolabeled oligonucleotides. We found that all five splice variants showed a distinct distribution pattern and, in some cases, in association with specific brain pathways. The most relevant differences were in hippocampal formation, medial habenula, basal ganglia, and area postrema, at both the regional and cellular level. The dorsal and median raphe nuclei exclusively contained PDE4D2 mRNA transcripts, probably located on serotonergic cells. PDE4D1 mRNA was expressed in some white matter cells. PDE4D1 and PDE4D2 mRNA splice forms presented a similar distribution in the area postrema, whereas for PDE4D4 and PDE4D5 the cellular distribution presented a complementary pattern. The differential expression of PDE4D mRNA splice variants in the area postrema is consistent with their possible involvement in emesis control and suggests new molecular targets for a more selective drug design.
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PMID:Differential distribution of PDE4D splice variant mRNAs in rat brain suggests association with specific pathways and presynaptical localization. 1212 47

Phosphodiesterases (PDE) belong to an important family of proteins that regulate the intracellular levels of cyclic nucleotide second messengers. Targeting PDE with selective inhibitors may offer novel therapeutic strategies in the treatment of various conditions, and in the context of respiratory disease these include asthma and chronic obstructive pulmonary disease (COPD). The rationale for such an approach stems, in part, from the clinical efficacy of theophylline, an orally active drug that is purportedly a nonselective PDE inhibitor. In addition, intracellular cyclic adenosine monophosphate (cAMP) levels regulate the function of many of the cells thought to contribute to the pathogenesis of respiratory diseases such as asthma and COPD, and these cells also selectively express PDE4. This has offered pharmaceutical companies the opportunity to selectively targeting these enzymes for the treatment of these diseases. Finally, the success of targeting PDE5 in the treatment of erectile dysfunction provides clinical proof of concept for the targeting of PDE in disease. Whether a 'Viagra' of the airways can be found for the treatment of asthma and COPD remains to be seen, but positive results from recent clinical studies examining the efficacy of selective PDE4 inhibitors such as cilomilast and roflumilast offer some optimism. However, one of the major issues to be resolved is the tolerability profile associated with this drug class that is a consequence of PDE4 inhibition. While cilomilast and roflumilast have low emetic potential they are not free from emesis and various strategies are being investigated in the hope of developing a PDE4 inhibitor without this adverse effect.
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PMID:Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease. 1463 78

SCH351591, a novel phosphodiesterase-4 inhibitor under investigation as a potential therapeutic for asthma and chronic obstructive pulmonary disease (COPD), was evaluated in a 3-month rising-dose study in Cynomolgus monkeys. Four groups, containing four monkeys/sex, received vehicle control or rising doses up to 12, 24, or 48 mg/kg of SCH351591 daily. Although initial exposure produced clinical signs of emesis, reduced food intake, and reduced body weight, tachyphylaxis to the emesis allowed dose escalation up to 48 mg/kg/day. Two monkeys died and 3 were sacrificed in moribund condition over the course of the study. Early mortality, involving monkeys dosed with 12 or 24 mg/kg, was attributed to sepsis (2 monkeys) or colon inflammation (3 monkeys). Leukocyte function assays on low- and mid-dose group survivors revealed an inhibition of T lymphocyte proliferation for 12 mg/kg group males and 24 mg/kg group monkeys of both sexes. Necropsy findings, unassociated with early mortality, included reduced size and weight of the thymus, depletion of body fat, red discoloration of the gastric mucosa, and perivascular hemorrhage of the stomach and heart. Stomach and heart gross findings were present in the high-dose group only. Histopathologic lesions, in addition to those attributed to concurrent bacterial infection, included thymic atrophy, serous atrophy of fat, myocardial degeneration and acute to chronic inflammation of small to medium-sized arteries in various organs and tissues including the heart, kidneys, stomach, salivary glands, pancreas, esophagus, gallbladder, and mesentery. The findings of this study demonstrate the potential of a PDE4 inhibitor to alter immunologic response as well as to produce arteriopathy in nonhuman primates.
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PMID:The toxicity of SCH 351591, a novel phosphodiesterase-4 inhibitor, in Cynomolgus monkeys. 1520 71

The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.
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PMID:Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: structure-activity relationship, optimization, and identification of a highly potent, well tolerated, PDE4 inhibitor. 1616 47

Phosphodiesterase (PDE)4 inhibitors are a novel class of drugs in development for the treatment of inflammatory airways diseases, including asthma, allergic rhinitis and chronic obstructive pulmonary disease. PDE4 inhibitors are potent anti-inflammatory agents both in vitro and in vivo, but few have successfully proceeded to phase II and III clinical trials, as a result of insufficient clinical efficacy and unacceptable side effects, including nausea and emesis, which have hampered their progression. A greater understanding of the molecular biology of PDE4 has led to the development of efficacious compounds with fewer side effects. This review focuses on how selective PDE4 inhibitors can advance the treatment of airways diseases and deal with the challenges that lie ahead.
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PMID:Selective phosphodiesterase 4 inhibitors in the treatment of allergy and inflammation. 1631 35

YM-393059, (+/-)-N-(4,6-dimethylpyrimidin-2-yl)-4-[2-(4-methoxy-3-methylphenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-1H-indol-1-yl]benzenesulfonamide difumarate, is a novel phosphodiesterase (PDE) inhibitor that inhibited the PDE7A isoenzyme with a high potency (IC50=14 nM) and PDE4 with a moderate potency (IC50=630 nM). In a cell-based assay, YM-393059 was found to inhibit anti-CD3 antibody, Staphylococcal enterotoxin B, and phytohaemagglutinin-induced interleukin (IL)-2 production in mouse splenocytes with IC50 values ranging from 0.48 to 1.1 microM. It also inhibited anti-CD3 antibody-induced interferon (IFN)-gamma and IL-4 production in splenocytes with IC50 values of 1.8 and 2.8 microM, respectively. YM-393059's inhibition of anti-CD3 antibody-stimulated cytokine (IL-2, IFN-gamma, and IL-4) production was 20- to 31-fold weaker than that of YM976, a selective PDE4 inhibitor. However, orally administered YM-393059 and YM976 inhibited anti-CD3 antibody-induced IL-2 production equipotently in mice. In addition, YM-393059 inhibited lipopolysaccharide-induced tumor necrosis factor-alpha production in vivo more potently than IL-2 (ED50 values of 2.1 mg/kg and 74 mg/kg). In contrast to YM976, YM-393059 did not shorten the duration of alpha2-adrenoceptor agonist-induced sleep in mice, which is a model for the assessment of the typical side effects caused by PDE4 inhibitors, nausea and emesis. YM-393059 is a novel and attractive compound for the treatment of a wide variety of T-cell-mediated diseases.
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PMID:The effects of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on T-cell-related cytokine production in vitro and in vivo. 1678 Aug 33


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