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Stefan Endres - One of the best experts on this subject based on the ideXlab platform.
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specific type iv phosphodiesterase inhibitor Rolipram mitigates experimental colitis in mice
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Gunther Hartmann, Christoph Bidlingmaier, Stefan Albrich, Katharina Tschoep, Hans A Lehr, Britta Siegmund, Johannes Schulze, Andreas Eigler, Stefan EndresAbstract:The specific type IV phosphodiesterase inhibitor Rolipram is a potent suppressor of tumor necrosis factor-α (TNF) synthesis. We examined the efficacy of Rolipram for the prevention and treatment of experimental colitis. To induce colitis, BALB/c mice received 5% dextran sulfate sodium in their drinking water continuously for up to 11 days. Colitis was quantified by a clinical activity score assessing weight loss, stool consistency, and rectal bleeding (range from 0 to 4); by colon length; by a semiquantitative histologic score (range from 0 to 6); and by detecting TNF concentration in colonic tissue by enzyme-linked immunosorbent assay. In a first protocol, Rolipram (10 mg/kg b.wt./day i.p.) was started on the same day as dextran sulfate sodium. Rolipram reduced the clinical activity of colitis (score 1.1 ± 0.3) compared with mice that did not receive Rolipram (2.4 ± 0.4; P = .041). Rolipram also partially reversed the reduction of colon length (without Rolipram, 12.4 ± 0.3 cm; with Rolipram, 15.4 ± 0.7 cm; P = .004) and improved the histologic score (1.5 ± 0.6 in Rolipram-treated mice versus 4.6 ± 0.5; P = .020). Rolipram suppressed colonic tissue TNF concentrations. The beneficial effect of Rolipram was confirmed in a second protocol in which dextran sulfate sodium exposure was discontinued on day 7 and Rolipram was administered from day 8 through day 15. These three series of experiments on a total of 153 mice documented the efficacy of Rolipram in both the prevention and treatment of experimental colitis.
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Rolipram, a specific type IV phosphodiesterase inhibitor, is a potent inhibitor of HIV-1 replication.
AIDS, 1995Co-Authors: Jonathan B. Angel, Bradford M. Saget, Sean P. Walsh, Tim F. Greten, Charles A. Dinarello, Paul R. Skolnik, Stefan EndresAbstract:OBJECTIVE To determine the effects of Rolipram, a specific type IV phosphodiesterase inhibitor, on tumor necrosis factor (TNF)-alpha production and HIV-1 replication. DESIGN TNF-alpha enhances HIV-1 replication in vitro; blocking TNF-alpha and thereby inhibiting HIV-1 replication may therefore potentially delay progression of HIV disease. Pentoxifylline is a non-specific phosphodiesterase inhibitor that blocks TNF-alpha synthesis and HIV-1 replication in vitro and has been shown in preliminary clinical studies to decrease viral replication in HIV-1-infected patients. Rolipram, which selectively inhibits the predominant phosphodiesterase isoenzyme of monocytes, inhibits lipopolysaccharide (LPS)-induced TNF-alpha with 500-fold greater potency than pentoxifylline. We, therefore, hypothesized that Rolipram would be a powerful inhibitor of HIV-1 replication. METHODS The effects of Rolipram and pentoxifylline on TNF-alpha production and HIV-1 replication were determined in infected and uninfected peripheral blood mononuclear cells (PBMC), in a chronically infected promonocytic cell line (U1) and in an acutely infected monocytic cell line (BT4A3.5). TNF-alpha was determined by specific radioimmunoassay and HIV-1 replication was measured by p24 antigen and HIV-1 mRNA production. RESULTS Rolipram inhibited TNF-alpha production in LPS- and phorbol myristate acetate (PMA)-stimulated PBMC and in PMA-stimulated U1 cells. Rolipram also inhibited HIV-1 replication in the U1 cell line, as well as in acutely infected PBMC and BT4A3.5 cells. Depending on the experimental conditions, Rolipram was 10-600 times more potent, on a molar basis, than pentoxifylline. CONCLUSION Rolipram is a potent inhibitor HIV-1 replication and therefore deserves further investigation as a potential therapeutic agent in the treatment of HIV-1-infected patients.
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the specific type iv phosphodiesterase inhibitor Rolipram suppresses tumor necrosis factor α production by human mononuclear cells
International Journal of Immunopharmacology, 1993Co-Authors: J Semmler, H Wachtell, Stefan EndresAbstract:Abstract Compounds suppressing the production of tumor necrosis factor-α are protective in animal modelsof septic shock. Recent studies demonstrated a beneficial effect of xanthine derivatives, which suppress tumor necrosis factor-α production by acting as non-specific cAMP phosphodiesterase inhibitors. In this experiment wwe tested the effect (±)-Rolipram (racemate) and its enantiomers on human mononuclear cells stimulated with lipopolysaccharide (LPS). Rolipram has a phenyl-pyrrolidinone structure, unrelated to the methylxanthines, and acts as a specific inhibitor of the type IV phosphodiesterase. Our results identify Rolipram as a remarkably potent suppressor of the LPS-induced synthesis of tumor necrosis factor-α. When compared to the non-specific inhibitor pentoxifylline, the IC 50 of (±)-Rolipram (130 nM) is more than 500 times lower. The influence of rolipra on tumor necdrosis factor-α production depended on the steric configuration of the molecule, since the (−)-enantiomer exhibited a five times lower IC 50 than the (+)-enantiomer. The inhibitory effect of all substances tested is selective for tumor necrosis factor-α rather than interleukin-1β, since interleukin-1β production is only slightly influenced.
Osamu Inoue - One of the best experts on this subject based on the ideXlab platform.
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effects of camp dependent protein kinase activator and inhibitor on in vivo Rolipram binding to phosphodiesterase 4 in conscious rats
Synapse, 2010Co-Authors: Tetsuji Itoh, Kohji Abe, Jinsoo Hong, Osamu Inoue, Victor W Pike, Robert B Innis, Masahiro FujitaAbstract:Rolipram is a selective inhibitor of phosphodiesterase-4 (PDE4), and positron emission tomography (PET) using [(11)C]Rolipram can monitor the in vivo activity of this enzyme that is part of the cAMP second messenger cascade. cAMP-dependent protein kinase (PKA) phosphorylates PDE4 and increases both enzyme activity and affinity for Rolipram. In the present PET study, we examined effects of PKA modulators in conscious rats on the binding of [(11)C](R)-Rolipram in comparison to the much less active enantiomer [(11)C](S)-Rolipram. Unilateral injection of a PKA activator (dibutyryl-cAMP) and a PKA inhibitor (Rp-adenosine-3',5'-cyclic monophosphorothioate) into the striatum significantly increased and decreased, respectively, the binding of [(11)C](R)-Rolipram. These effects were not caused by changes in blood flow or delivery of radioligand to brain, since these agents had no effect on the binding of [(11)C](S)-Rolipram binding. These results support the value of measuring in vivo [(11)C](R)-Rolipram binding in brain to assess responses to physiological or pharmacological challenges to the cAMP second messenger system.
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pet measurement of the in vivo affinity of 11c r Rolipram and the density of its target phosphodiesterase 4 in the brains of conscious and anesthetized rats
The Journal of Nuclear Medicine, 2009Co-Authors: Tetsuji Itoh, Kohji Abe, Jinsoo Hong, Osamu Inoue, Victor W Pike, Robert B Innis, Sami S Zoghbi, Masao Imaizumi, Masahiro FujitaAbstract:A variety of phosphodiesterases hydrolyze and terminate the effects of the intracellular second messenger 3′,5′-cyclic adenosine monophosphate (cAMP). Phosphodiesterase subtype 4 (PDE4) is particularly abundant in the brain and has been imaged with 11C-(R)-Rolipram, a selective inhibitor of PDE4. We sought to measure in vivo both the binding site density (Bmax) and the radioligand affinity (1/KD) of 11C-(R)-Rolipram in the rat brain. We also studied 2 critical factors in small-animal PET scans: the influence of anesthesia and the difference in binding under in vivo and in vitro conditions. Methods In vivo, Bmax and KD were measured in PET saturation experiments by the administration of 11C-(R)-Rolipram and various doses of carrier (R)-Rolipram in conscious and isoflurane-anesthetized rats. The metabolite-corrected arterial input function was measured in each scan. To image conscious rats, the head of the rat was fixed in a holder and the animals were trained to comply with this apparatus. Bound and free (R)-Rolipram levels were calculated under transient equilibrium conditions (i.e., at the time of peak specific binding).
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Effect of Rolipram on relative ^14C-deoxyglucose uptake in inflammatory lesions and skeletal muscle
European Journal of Nuclear Medicine and Molecular Imaging, 2005Co-Authors: Miho Shukuri, Masahiro Terai, Rie Hosoi, Tsunehiko Nishimura, Antony Gee, Osamu InoueAbstract:Purpose ^18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has become a useful imaging tool for inflammatory diseases. In this study we investigated the effects of Rolipram, a selective phosphodiesterase type 4 inhibitor, on^ 14C-deoxyglucose (DG) uptake in inflammatory lesions and other normal tissues, and attempted to improve the inflammation/muscle ratio. Methods To induce inflammation, mice were inoculated with turpentine oil. Inflammation-bearing mice were pretreated with Rolipram (3 mg/kg i.p. or i.v.), and the effect on^ 14C-DG uptake was measured using a tissue dissection method and autoradiography. The inflammatory tissue samples were stained with haematoxylin and eosin. Results Rolipram (3 mg/kg i.p.) significantly decreased ^14C-DG uptake in normal tissues like brain, heart and skeletal muscle (brain 31%, heart 60%, skeletal muscle 61%). On the other hand, ^14C-DG uptake in inflammatory lesions was not significantly altered by pretreatment with Rolipram. The inflammation/muscle ratio of ^14C-DG uptake (30 min after tracer injection) was enhanced from 1.1 to 2.8 by Rolipram. An autoradiographic study revealed heterogeneous distributions of ^14C-DG in the inflammatory lesions and skeletal muscle of animals that were not treated with Rolipram. Pretreatment with Rolipram significantly attenuated the intramuscular distribution of ^14C-DG, producing a relatively homogeneous distribution of radioactivity. Conclusion These results indicate that Rolipram decreased^ 14C-DG uptake in skeletal muscle by activation of the adenosine 3′,5′-cyclic monophosphate system, whereas^ 14C-DG uptake in inflammatory lesions was not significantly altered. Therefore, Rolipram may be a valuable tool for improving the visualisation of inflammatory lesions in clinical PET studies employing FDG.
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Effect of Rolipram on muscarinic acetylcholine receptor binding in the intact mouse brain.
Journal of Neural Transmission, 2003Co-Authors: Rie Hosoi, Kaoru Kobayashi, M. Ishikawa, Antony D. Gee, Masatoshi Yamaguchi, Osamu InoueAbstract:The effect of Rolipram, a selective inhibitor of phosphodiesterase type 4 (PDE4) and elevating cyclic AMP (cAMP), on in vivo and in vitro 3H-N-methylpiperidyl benzilate (3H-NMPB) binding to muscarinic acetylcholine receptors in the mouse brain was examined. Rolipram significantly decreased in vivo 3H-NMPB binding in the cerebral cortex, hippocampus and striatum, whereas in vitro 3H-NMPB binding in these regions was not altered. Saturation experiments on in vivo binding in conjunction with the kinetic analysis revealed that the apparent association rate constant (kon) of 3H-NMPB binding in vivo was significantly decreased by Rolipram. A similar decrease in the apparent association rate constant (kon) by Rolipram was reported for dopamine D1 and D2 receptor binding in vivo. These results indicate that Rolipram plays an important role in the global modulation of apparent rates of ligand-receptor interactions in the intact brain.
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Rolipram depresses [(3)H]2-deoxyglucose uptake in mouse brain and heart in vivo.
European Journal of Nuclear Medicine and Molecular Imaging, 2002Co-Authors: Megumi Ishikawa, Tsunehiko Nishimura, Rie Hosoi, Kaoru Kobayashi, Osamu InoueAbstract:The effects of systemic administration of Rolipram, a selective phosphodiesterase type 4 inhibitor, on [3H]2-deoxyglucose (DG) uptake in brain and peripheral tissues were examined. Rolipram significantly and dose-dependently decreased [3H]DG uptake in brain, heart and skeletal muscle. In contrast, the radioactivity concentrations in the plasma of Rolipram-treated mice were significantly higher than those of control mice at all times after injection of the tracer. In the kinetic study, the initial uptake of [3H]DG in brain was decreased by Rolipram, whereas no significant differences were observed in the uptake in heart and skeletal muscle. However, radioactivity concentrations in the brain, heart and skeletal muscle 30 min after the injection of [3H]DG were significantly lowered by Rolipram to about 60%, 10% and 10% of control values, respectively. The uptake of [13N]ammonia in brain and heart of Rolipram-treated mice was slightly decreased, which indicated that Rolipram diminished both cerebral and cardiac blood flow. These results indicate that the phosphorylation process via hexokinase rather than the transport of [3H]DG might be depressed by Rolipram. Together with the previous observations that inhibition of protein kinase A (PKA) markedly enhanced [14C]DG uptake in rat brain, these results indicate an important role of the cAMP/PKA systems in the regulation of glucose metabolism in the living brain as well as in peripheral tissues such as the heart and skeletal muscle.
Theodore J. Torphy - One of the best experts on this subject based on the ideXlab platform.
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Association of the anti-inflammatory activity of phosphodiesterase 4 (PDE4) inhibitors with either inhibition of PDE4 catalytic activity or competition for [3H]Rolipram binding
Biochemical Pharmacology, 1996Co-Authors: Mary S. Bamette, Lenora B. Cieslinski, Joan O'leary Bartus, Miriam Burman, Siegfried B. Christensen, Klaus M. Esser, Uma Prabhakar, Julia A. Rush, Theodore J. TorphyAbstract:Abstract Phosphodiesterase 4 (PDE4) inhibitors are novel anti-inflammatory compounds. Unfortunately, the archetypal PDE4 inhibitor Rolipram produces central nervous system and gastrointestinal side-effects. To exploit these agents, we need to identify PDE4 inhibitors that retain the anti-inflammatory activity with a reduced potential to elicit unwanted side-effects. PDE4 possesses both cyclic AMP catalytic activity that is inhibitable by Rolipram and a high affinity binding site for Rolipram. The function of this high affinity Rolipram binding site is unclear; however, certain pharmacological effects of PDE4 inhibitors are associated with competition for this site. Since PDE4 inhibitors suppress both monocyte and neutrophil activation, the present experiments were carried out to establish a correlation between suppression of monocyte activation [tumor necrosis factor alpha (TNFa) formation] or suppression of neutrophil activation (degranulation) with inhibition of either PDE4 catalytic activity or [ 3 H]Rolipram binding. Suppression of TNFa formation demonstrated a strong correlation with inhibition of PDE4 catalytic activity ( r = 0.87; P P r = 0.21, P > 0.5; Spearman's Rho = 0.16, P > 0.5). Suppression of neutrophil degranulation was not associated with inhibition of PDE4 catalytic activity ( r = 0.25, P > 0.4; Spearman's Rho = 0.33, P > 0.2), but was associated with inhibition of [ 3 H]Rolipram binding ( r = 0.68, P P = 0.06). These results indicate that anti-inflammatory effects of PDE4 inhibitors can be associated with either inhibition of PDE4 catalytic activity or high affinity Rolipram binding.
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inhibition of antigen induced bronchoconstriction and eosinophil infiltration in the guinea pig by the cyclic amp specific phosphodiesterase inhibitor Rolipram
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: D C Underwood, R R Osborn, L B Novak, Jane K Matthews, S J Newsholme, Bradley J Undem, J M Hand, Theodore J. TorphyAbstract:Selective inhibition of the low Km cyclic AMP-specific phosphodiesterase has been shown to inhibit inflammatory cell function and relax airway smooth muscle. These studies were conducted to characterize the bronchodilator and anti-inflammatory activity of Rolipram, an archetypical cyclic AMP-specific phosphodiesterase inhibitor, in in vitro and in vivo guinea pig airway models. In isolated tracheal rings from ovalbumin (OA)-sensitive guinea pigs, both R- and S-enantiomers of Rolipram (1 microM) significantly antagonized OA-induced contractions. In contrast, neither enantiomer at concentrations up to 1 microM significantly inhibited histamine- or LTD4-induced contractions. In superfusion and mediator release experiments, both enantiomers of Rolipram significantly reduced antigen-induced prostaglandin D2 release, but had minimal effect on histamine release. In anesthetized, ventilated OA-sensitive guinea pigs, racemic Rolipram or enantiomers reduced OA-induced bronchoconstriction with ID50 values of approximately 0.25 mg/kg i.v. Histamine- and leukotriene D4-induced bronchoconstriction were not affected by doses of Rolipram which abolished the response to OA. Higher doses (3-10 mg/kg) reduced histamine-, but not the leukotriene D4-induced bronchoconstriction. In conscious OA-sensitive guinea pigs, intragastric pretreatment with Rolipram dose-dependently reduced both the OA-induced decreases in specific conductance as well as the corresponding pulmonary eosinophil influx as assessed by both bronchoalveolar lavage and histological evaluation. Therefore, Rolipram produces significant inhibition of antigen-induced bronchoconstrictor and inflammatory responses, thus providing strong evidence that this pharmacological approach may be of significant therapeutic value in allergic asthma.(ABSTRACT TRUNCATED AT 250 WORDS)
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Effect of selective phosphodiesterase type IV inhibitor, Rolipram, on fluid and cellular phases of inflammatory response.
Inflammation, 1993Co-Authors: Don E. Griswold, Edward F. Webb, John J. Breton, John R. White, Paul J. Marshall, Theodore J. TorphyAbstract:The antiinflammatory activity of Rolipram, a selective inhibitor of the cyclic AMP-specific phosphodiesterase (PDE IV), was studied. Rolipram did not inhibit 5-lipoxygenase activity but did inhibit human monocyte production of leukotriene B4 (LTB4, IC50 3.5 μM). Likewise, murine mast cell release of leukotriene C4 and histamine was inhibited. In vivo, Rolipram inhibited arachidonic acid-induced inflammation in the mouse, while the lowKm-cyclic-GMP PDE inhibitor, zaprinast, did not inhibit. Rolipram had a modest effect on LTB4 production in the mouse, but markedly reduced LTB4-induced PMN infiltration. Beta-adrenergic receptor activation of adenylate cyclase was important for Rolipram antiinflammatory activity since beta blockade abrogated arachidonic acid-induced inflammation. Thus, the antiinflammatory profile of Rolipram is novel and may result from inhibition of PMN function and perhaps vasoactive amine release and leukotriene biosynthesis. These actions may be dependent upon endogenous beta-adrenergic activity and are likely mediated through inhibition of PDE IV.
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Coexpression of human cAMP-specific phosphodiesterase activity and high affinity Rolipram binding in yeast.
The Journal of biological chemistry, 1992Co-Authors: Theodore J. Torphy, Lenora B. Cieslinski, J. M. Stadel, M Burman, M M Mclaughlin, J. R. White, George P. LiviAbstract:Abstract Studies by various investigators have demonstrated that the low Km, cAMP-specific phosphodiesterase (PDE IV) is selectively inhibited by a group of compounds typified by Rolipram and Ro 20-1724. In addition to inhibiting the catalytic activity of PDE IV, Rolipram binds to a high affinity binding site present in brain homogenates. Although it has been assumed that the high affinity Rolipram-binding site is PDE IV, no direct evidence has been produced to support this assumption. The present studies were undertaken to determine whether the Rolipram-binding site is coexpressed with PDE IV catalytic activity in Saccharomyces cerevisiae genetically engineered to express human recombinant monocytic PDE IV (hPDE IV). Expressing hPDE IV cDNA in yeast resulted in a 20-fold increase in PDE activity that was evident within 1 h of induction and reached a maximum by 3-6 h. The recombinant protein represented hPDE IV as judged by its immunoreactivity, molecular mass (approximately 88 kDa), kinetic characteristics (cAMP Km = 3.1 microM; cGMP Km greater than 100 microM), sensitivity to Rolipram (Ki = 0.06 microM), and insensitivity to siguazodan (PDE III inhibitor) and zaprinast (PDE V inhibitor). Saturable, high affinity [3H] (R)-Rolipram-binding sites (Kd = 1.0 nM) were coexpressed with PDE activity, indicating that both binding activity and catalytic activity are properties of the same protein. A limited number of compounds were tested for their ability to inhibit hPDE IV catalytic activity and compete for [3H](R)-Rolipram binding. Analysis of the data revealed little correlation (r2 = 0.35) in the structure-activity relationships for hPDE IV inhibition versus competition for [3H] (R)-Rolipram binding. In fact, certain compounds (e.g. (R)-Rolipram Ro 20-1724) possessed a 10-100-fold selectivity for inhibition of [3H] (R)-Rolipram binding over hPDE IV inhibition, whereas others (e.g. dipyridamole, trequinsin) possessed a 10-fold selectivity for PDE inhibition. Thus, although the results of these studies demonstrate that hPDE IV activity and high affinity [3H](R)-Rolipram binding are properties of the same protein, they do not provide clear cut evidence linking the binding site with the PDE inhibitory activity of Rolipram and related compounds.
Gerald L Mandell - One of the best experts on this subject based on the ideXlab platform.
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the specific type iv phosphodiesterase inhibitor Rolipram combined with adenosine reduces tumor necrosis factor α primed neutrophil oxidative activity
International Journal of Immunopharmacology, 1995Co-Authors: Gail W Sullivan, Holliday T Carper, Gerald L MandellAbstract:Abstract Monocytes and macrophages produce tumor necrosis factor-α (TNFα) in response to microbial products including endotoxin. TNFα is a potent primer of neutrophil (PMN) oxidative activity. Certain xanthine phosphodiesterase (PDE) inhibitors such as pentoxifylline have been shown to inhibit stimulated oxidative activity in PMN. In the present study, the non-xanthine PDE type IV inhibitor Rolipram (4-[3′-cyclopentyloxy-4′-methoxyphenyl]-2-pyrrolidone) alone and in combination with adenosine is examined as a potential modulator of TNFα-primed PMN oxidative activity. Attainable in vivo concentrations of Rolipram and physiological concentrations of adenosine alone and together synergistically decreased rhTNFα-primed suspended PMN oxidative activity stimulated by the chemoattractant f-met-leu-phe. The Rolipram effect was reversible by washing, and Rolipram had a comparable effect if added before or after priming, indicating that its effect was on the primed response rather than on priming per se. In addition, Rolipram especially when combined with adenosine, decreased rhTNFα-stimulated PMN adherence to a fibrinogen-coated surface, and the oxidative burst of rhTNFα-stimulated adherent PMN. The specific adenosine A2a receptor agonists CGS 21680 and WRC-0474 had comparable activity to adenosine in these experiments. Adenosine (or CGS 21680) combined with Rolipram synergistically increased f-met-leu-phe-stimulated PMN cAMP content. The effects of both adenosine and Rolipram with adenosine could be only partly counteracted by treatment of the PMN with the protein kinase A inhibitor KT 5720, indicating that protein phosphorylation is only partially involved. Rolipram activity was about 1000x (by molar concentration) greater than pentoxifylline in comparable assays. Thus, Rolipram, especially when combined with adenosine, has potent modulating effects on PMN activation and may be useful in decreasing inflammatory tissue damage in patients with sepsis.
Jeenene E Tickner - One of the best experts on this subject based on the ideXlab platform.
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synthesis and in vitro profile of a novel series of catechol benzimidazoles the discovery of potent selective phosphodiesterase type iv inhibitors with greatly attenuated affinity for the 3h Rolipram binding site
Bioorganic & Medicinal Chemistry Letters, 1995Co-Authors: John B Cheng, Kelvin Cooper, Allen J Duplantier, James F Eggler, Kenneth G Kraus, Sally C Marshall, Anthony Marfat, Hiroko Masamune, J T Shirley, Jeenene E TicknerAbstract:Abstract The synthesis and biological properties of a novel series of potent and selective phosphodiesterase type IV (PDE IV) inhibitors are described. These catechol benzimidazoles were designed from Rolipram and initial compounds reflected a similarly high affinity for the [ 3 H]Rolipram b binding site (500 to 1000X greater affinity for the [ 3 H]Rolipram binding site over the PDE IV inhibitory site). However, SAR studies on the 3-alkoxy position revealed that this [ 3 H]Rolipram binding site affinity could be attenuated, while potentiating the PDE IV inhibitory activity. This resulted in the 2-indanyl analog 13 which is a potent, selective PDE IV inhibitor with a 15X differential in favor of PDE IV binding.
