Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis, structure-activity relationships, and biological properties of a novel series of potent and selective phosphodiesterase type 4 (PDE4) inhibitors are described. These new aminodiazepinoindoles displayed in vitro PDE4 activity with submicromolar IC(50) values and PDE4 selectivity vs PDE1, -3, and -5. Specifically, one compound (CI-1044, 10e) provided efficient in vitro inhibition of TNFalpha release from hPBMC and hWB with IC(50) values of 0.34 and 0.84 microM, respectively. This compound was found to exhibit potent in vivo activity in antigen-induced eosinophil recruitment in Brown-Norway rats (ED(50) = 3.2 mg/kg po) and in production of TNFalpha in Wistar rats (ED(50) = 2.8 mg/kg po). No emetic side effects at therapeutic doses were observed in ferrets.
 ...
PMID:Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6, 7,1-hi]indoles: discovery of potent, selective phosphodiesterase type 4 inhibitors. 1112 95

We have investigated the bronchodilator and anti-inflammatory properties of roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-dichloropyrid-4-yl]-benzamide), a novel, highly potent, and selective phosphodiesterase 4 (PDE4) inhibitor. Additionally, we compared the effects of roflumilast and its N-oxide, the primary metabolite in vivo, with those of the PDE4 inhibitors piclamilast, rolipram, and cilomilast. Roflumilast inhibited the ovalbumin-evoked contractions of tracheal chains prepared from sensitized guinea pigs (EC(50) = 2 x 10(-7) M) but showed no relaxant effect on tissues contracted spontaneously. In spasmogen-challenged rats and guinea pigs, intravenously administered roflumilast displayed bronchodilatory activity (ED(50) = 4.4 and 7.1 micromol/kg, respectively). Furthermore, roflumilast dose dependently attenuated allergen-induced bronchoconstriction in guinea pigs (ED(50) = 0.1 micromol/kg i.v.). Roflumilast given orally (ED(50) = 1.5 micromol/kg) showed equal potency to its N-oxide (ED(50) = 1.0 micromol/kg) but was superior to piclamilast (ED(50) = 8.3 micromol/kg), rolipram (ED(50) = 32.5 micromol/kg), and cilomilast (ED(50) = 52.2 micromol/kg) in suppressing allergen-induced early airway reactions. To assess the anti-inflammatory potential of orally administered roflumilast, antigen-induced cell infiltration, total protein, and TNFalpha concentration in bronchoalveolar lavage fluid of Brown Norway rats were determined. Roflumilast and its N-oxide equally inhibited eosinophilia (ED(50) = 2.7 and 2.5 micromol/kg, respectively), whereas the reference inhibitors displayed lower potency (ED(50) = 17-106 micromol/kg). Besides, orally administered roflumilast abrogated LPS-induced circulating TNFalpha in the rat (ED(50) = 0.3 micromol/kg), an effect shared by its N-oxide, with both molecules exhibiting 8-, 25-, and 310-fold superiority to piclamilast, rolipram, and cilomilast, respectively. These results, coupled with the in vitro effects of roflumilast on inflammatory cells, suggest that roflumilast represents a potential new drug for the treatment of asthma and chronic obstructive pulmonary disease.
 ...
PMID:In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. 1125 55

We investigated the pharmacology of a new class of phosphodiesterase 4 (PDE4) inhibitor, 6,8-disubstituted 1,7-naphthyridines, by using 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic acid (NVP-ABE171) as a representative compound and compared its potency with the most advanced PDE4 inhibitor, undergoing clinical trials, Ariflo [cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl-r-1-cyclohexanecarboxylic acid)]. NVP-ABE171 inhibited the activity of phosphodiesterase 4A, 4B, 4C, and 4D with respective IC(50) values of 602, 34, 1230, and 1.5 nM. Ariflo was about 40 times less potent. In human cells, NVP-ABE171 inhibited the eosinophil and neutrophil oxidative burst, the release of cytokines by T cells, and the tumor necrosis factor-alpha release from monocytes, in the nanomolar range. Ariflo presented a similar inhibition profile but was 7 to 50 times less potent. In BALB/c mice challenged with lipopolysaccharide, NVP-ABE171 inhibited the airway neutrophil influx and activation with an ED(50) in the range of 3 mg/kg. Ariflo was inactive up to a dose of 10 mg/kg. In ovalbumin sensitized Brown Norway rats, NVP-ABE171 inhibited the lipopolysaccharide-induced airway neutrophil influx and activation (ED(50) of 0.2 mg/kg) and the ovalbumin-induced airway eosinophil influx and activation (ED(50) of 0.1 mg/kg). Ariflo was about 100 times less potent in both models. In the ovalbumin model, NVP-ABE171 had a duration of action of more than 24 h. NVP-ABE171 is a novel PDE4 inhibitor that shows activity both in vitro on human inflammatory cells and in vivo in animal models of lung inflammation. This compound class may have potential for the treatment of airway inflammatory conditions such as asthma and chronic obstructive pulmonary diseases.
 ...
PMID:Pharmacological profile of a novel phosphodiesterase 4 inhibitor, 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic acid (NVP-ABE171), a 1,7-naphthyridine derivative, with anti-inflammatory activities. 1190 80

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.
 ...
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

Physiological aging is a significant risk factor in the on-set of male erectile dysfunction (ED) and an imbalance in factors that modulate cavernosal smooth-muscle tone may play a role in these altered penile hemodynamic mechanisms. To evaluate the association between aging and male erectile function, we monitored neurogenic erectile response and its correlation to systemic arterial pressure changes in old (21-23 months of age) vs young (6-9 months of age) Brown-Norway (BN) rats. We tested the hypothesis that age-associated ED is due to unregulated vasoconstrictive tone, contributed in part by an increased Rho-kinase activity, and that antagonism of Rho-kinase activity attenuates the age-related decline in male erectile function. We also examined the hypothesis that a combination of Rho-kinase antagonism and phosphodiesterase-5 (PDE-5) inhibition has a synergistic effect in improving the erectile response in these aging animals. Erectile function in old BN rats was evaluated before and after intracavernosal injection of a specific inhibitor of Rho-kinase (Y-27632) alone or in combination with zaprinast, a PDE-5 inhibitor. Erectile capabilities of the young and old BN rat groups were significantly different in corpus cavernosum pressure response after electrical-field stimulation of the major pelvic ganglion. Y-27632 administration attenuated the aging-related changes in male erectile function seen in BN rats. Rho-kinase antagonism and PDE-5 inhibition had a synergistic effect in improving erectile function in old rats. Our data indicate that aging leads to impairment in the neurogenic erectile response in BN rats involving a possible derangement in penile hemodynamic mechanisms of the erectile tissue. Rho-kinase inhibition may be of value in treating age-related ED.
 ...
PMID:Rho-kinase inhibition improves erectile function in aging male Brown-Norway rats. 1571 24

Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor with anti-inflammatory activity. We compared the anti-inflammatory effects of roflumilast with those of PDE4 inhibitors rolipram, piclamilast, and cilomilast in ovalbumin (OVA)-sensitized and challenged Brown-Norway rats. Animals were treated orally 1h before OVA challenge with roflumilast (0.3, 1.0, and 3.0mg/kg), rolipram (0.8, 2.8, and 8.3mg/kg), piclamilast (10.0, 20.0, and 30.0mg/kg), or cilomilast (10.3, 34.3, and 103.0mg/kg). Airway hyperresponsiveness (AHR) against adenosine was investigated by measuring airway resistance 200min after OVA challenge. Subsequently, neutrophil influx and tumor necrosis factor-alpha (TNF-alpha) release in the lungs were determined by bronchoalveolar lavage. Direct bronchodilation at the time point of AHR assessment by PDE4 inhibitors was examined in serotonin-challenged animals. Evaluation of neutropenic animals or treatment with anti-TNF-alpha antibody revealed that AHR was independent of neutrophil accumulation or TNF-alpha release. Roflumilast (50% inhibitory dose [ID(50)]=1.5mg/kg) inhibited AHR 3-, 16-, and 27-fold more potently than rolipram, piclamilast, and cilomilast, respectively. Likewise, roflumilast was a more potent inhibitor of neutrophil influx (ID(50)=0.9mg/kg) than rolipram (ID(50)=6.9mg/kg), piclamilast (ID(50)=28.1mg/kg), or cilomilast (ID(50)=37.7mg/kg). Roflumilast, rolipram, and piclamilast-but not cilomilast-suppressed OVA-induced TNF-alpha release in a dose-dependent manner. Roflumilast (ID(50)=0.9mg/kg) exhibited 9- and 23-fold more potent inhibition of TNF-alpha release than rolipram and piclamilast, respectively. Roflumilast did not inhibit serotonin-induced bronchoconstriction 4.5h after administration, suggesting that inhibition of AHR by roflumilast results from anti-inflammatory, not bronchodilatory, effects. This study suggests that roflumilast has anti-inflammatory action and provides rationale for the investigation of roflumilast in asthmatic patients.
 ...
PMID:Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors. 1625 50

3-Nitrotyrosine (3-NT) is a useful biomarker of increasing oxidative stress and protein nitration during biological aging. The proteomic analysis of cerebellar homogenate from Fisher 344/Brown Norway (BN/F1) rats shows an age-dependent increase in protein nitration, monitored by western-blot analysis after two-dimensional gel electrophoresis (2DE), mainly in the acidic region. Analysis of in-gel digests by nanoelectrospray (NSI)-MS/MS resulted in the identification of 16 putatively nitrated proteins. The selective isolation of nitrated proteins using immunoprecipitation, followed by SDS-PAGE and in-gel digest/NSI-MS/MS analysis led to the identification of 22 putatively nitrated proteins, of which 7 were identical to those detected after 2DE. When proteins were separated by solution isoelectrofocusing and analyzed by NSI MS/MS, we obtained MS/MS spectra of 3-NT containing peptides of four proteins - similar to ryanodine receptor 3, low density lipoprotein related receptor 2, similar to nebulin-related anchoring protein isoform C and 2,3 cyclic nucleotide 3-phosphodiesterase. Although the functional consequences of protein nitration for these targets are not yet known, our proteomic experiments serve as a first screen for the more targeted analysis of nitrated proteins from aging cerebellum for functional characterization.
 ...
PMID:Proteomic analysis of protein nitration in rat cerebellum: effect of biological aging. 1725 26

Orally active phosphodiesterase 4 (PDE4) inhibitors have been developed for the treatment of asthma and chronic obstructive pulmonary disorders (COPD) although their full development has been limited by adverse side effects. Administration of PDE4 inhibitors by inhalation may improve their therapeutic index, but limited information exists on the efficacy of inhaled PDE4 inhibitors to improve lung function. In this study in ovalbumin-sensitized Brown Norway rats, roflumilast was given either intratracheally or by nose-only inhalation and changes in lung function (forced vital capacity, FVC; peak expiratory flow, PEF) and inflammatory cell influx (total cells, eosinophils and neutrophils) into the bronchoalveolar lavage (BAL) fluid were evaluated 24 h after allergen challenge. Intratracheal roflumilast, given 5 h before antigen challenge, inhibited the antigen-induced reductions in FVC (ED50 = 140 microg/kg, i.t.) and total cells appearing in the bronchoalveolar lavage fluid (ED50 = 50 microg/kg, i.t.). By the nose-only inhalation route, roflumilast reduced the bronchoalveolar lavage fluid total cells (ED50 = 10 microg/kg, estimated pulmonary deposition). Intratracheal roflumilast (600 microg/kg, i.t.) was also given to rats 24 h after the antigen challenge and reversed the antigen-induced reductions of FVC by 38% at 1 h, 54% at 5 h and 71% by 16 h. Intratracheal roflumilast also reduced the number of inflammatory cells in the bronchoalveolar lavage fluid and reduced the interstitial airway edema caused by the antigen challenge. These results support the development of inhaled PDE4 inhibitors for the treatment of asthma and COPD, particularly for the improvement of lung function.
 ...
PMID:Effect of inhaled roflumilast on the prevention and resolution of allergen-induced late phase airflow obstruction in Brown Norway rats. 1761 Aug 65

Eosinophils play a major role in the development and severity of asthma. Robust and rapid preclinical animal models are desirable to profile novel therapeutics inhibiting the influx of eosinophils into the airways. To develop a rapid, airway eosinophil recruitment model in the rat, Brown-Norway (BN) rats were immunised with ovalbumin (OVA)/alum on day 0, 1 and 2 and challenged with OVA aerosol on day 5 and 6. On day 7 bronchoalveolar lavage fluid (BALF) was analysed for eosinophil numbers, eosinophil peroxidase (EPO) activity and cytokines. Lung sections were also examined. The immunised animals showed a strong selective influx of eosinophils into the airways correlating with enhanced EPO activity, Interleukin (IL-4), IL-5 and monocytes chemo attractant protein levels in the BALF in comparison to sham-sensitised rats. In addition the immunised rats developed goblet cell metaplasia in the lung and showed OVA specific IgG1 and IgE levels in the serum but no airway hyperreactivity after metacholine challenge. Airway inflammation was suppressed by applying the steroids Budesonide (intra tracheally) and Prednisolone (per orally), Roflumilast a phosphodiesterase-4 inhibitor, and the H1 receptor antagonists Epinastine and Ketotifen. Montelukast, a Leukotriene receptor antagonist and Chromoglycate, a mast cell stabiliser, had no effect in this model. In summary, in this novel preclinical rat model therapeutics expected to inhibit the development of airway eosinophilia can rapidly be tested.
 ...
PMID:Development and characterisation of a novel and rapid lung eosinophil influx model in the rat. 1849 Jan 84

The Puerto Rican Racer Alsophis portoricensis is known to use venom to subdue lizard prey, and extensive damage to specific lizard body tissues has been well documented. The toxicity and biochemistry of the venom, however, has not been explored extensively. We employed biological assays and proteomic techniques to characterize venom from A. portoricensis anegadae collected from Guana Island, British Virgin Islands. High metalloproteinase and gelatinase, as well as low acetylcholinesterase and phosphodiesterase activities were detected, and the venom hydrolyzed the alpha-subunit of human fibrinogen very rapidly. SDS-PAGE analysis of venoms revealed up to 22 protein bands, with masses of approximately 5-160 kDa; very little variation among individual snakes or within one snake between venom extractions was observed. Most bands were approximately 25-62 kD, but MALDI-TOF analysis of crude venom indicated considerable complexity in the 1.5-13 kD mass range, including low intensity peaks in the 6.2-8.8 kD mass range (potential three-finger toxins). MALDI-TOF/TOF MS analysis of tryptic peptides confirmed that a 25 kDa band was a venom cysteine-rich secretory protein (CRiSP) with sequence homology with tigrin, a CRiSP from the natricine colubrid Rhabdophis tigrinus. The venom was quite toxic to NSA mice (Mus musculus: LD(50)=2.1 microg/g), as well as to Anolis lizards (A. carolinensis: 3.8 microg/g). Histology of the venom gland showed distinctive differences from the supralabial salivary glands (serous vs. mucosecretory), and like the Brown Treesnake (Boiga irregularis), another rear-fanged snake, serous secretory cells are arranged in densely packed secretory tubules, with little venom present in tubule lumina. These results clearly demonstrate that venom from A. portoricensis shares components with venoms of front-fanged snakes as well as with other rear-fanged species. Venom from A. portoricensis, in particular the prominent metalloproteinase activity, likely serves an important trophic function by facilitating prey handling and predigestion of prey.
 ...
PMID:Biological and proteomic analysis of venom from the Puerto Rican Racer (Alsophis portoricensis: Dipsadidae). 1983 6


<< Previous 1 2 3 Next >>