The Experts below are selected from a list of 1689 Experts worldwide ranked by ideXlab platform
Siegfried B. Christensen - One of the best experts on this subject based on the ideXlab platform.
-
The ability of Phosphodiesterase IV inhibitors to suppress superoxide production in guinea pig eosinophils is correlated with inhibition of Phosphodiesterase IV catalytic actIVity.
The Journal of pharmacology and experimental therapeutics, 1995Co-Authors: M S Barnette, C.d. Manning, Lenora B. Cieslinski, Miriam Burman, Siegfried B. Christensen, T. J. TorphyAbstract:Elevation of cyclic AMP (cAMP) content inhibits eosinophil function. Because Phosphodiesterase IV (PDE IV) appears to be the major PDE isozyme present in eosinophils, inhibitors of this isozyme should suppress eosinophil actIVation. Previous studies on PDE IV have revealed that this enzyme possesses both cAMP catalytic actIVity that is inhibitable by rolipram, a prototypical PDE IV inhibitor, and a high-affinity binding site for rolipram. The function of this high-affinity rolipram binding site relatIVe to the inhibitory action of compounds is not clear because the rank order potency of PDE IV inhibitors for competing with [3H]-rolipram binding is distinct from that for inhibiting cAMP hydrolysis. Consequently, the present experiments were carried out to fulfill the following objectIVes: 1) to determine whether PDE IV inhibitors suppress eosinophil function and, if so, 2) to establish a correlation between this functional actIVity and inhibition of PDE IV catalytic actIVity or interaction with the high-affinity rolipram binding site. Various PDE inhibitors produced approximately 60% maximal inhibition of formylmethionine-leucine-phenylalanine-induced superoxide anion production, so that IC30 concentrations were used as a basis to compare the potency of various PDE inhibitors. SelectIVe PDE IV inhibitors were the most potent compounds tested. PDE inhibitors selectIVe for other isozymes were devoid of actIVity or considerably less potent.(ABSTRACT TRUNCATED AT 250 WORDS)
-
the crystal structure absolute configuration and Phosphodiesterase inhibitory actIVity of 1 4 bromobenzyl 4 3 cyclopentyloxy 4 methoxyphenyl pyrrolidin 2 one
Journal of Medicinal Chemistry, 1993Co-Authors: Paul W Baures, Lenora B. Cieslinski, Drake S Eggleston, Karl F Erhard, Theodore J Torphy, Siegfried B. ChristensenAbstract:Chiral HPLC resolution of the Phosphodiesterase IV (PDE IV) inhibitor rolipram (1) provided (-)-1, and this enantiomer was converted into its 1-(4-bromobenzyl) derIVatIVe, (+)-2. X-ray structural analysis of (+)-2 established the absolute configuration as R, which provides the first direct evidence for a previously assumed assignment of configuration. The crystal structure of (+)-2 and the PDE inhibitory actIVity of both enantiomers of 2 are discussed in the context of a previously proposed topological model.
-
The crystal structure, absolute configuration, and Phosphodiesterase inhibitory actIVity of (+)-1-(4-bromobenzyl)-4-(3-(cyclopentyloxy)- 4-methoxyphenyl)-pyrrolidin-2-one.
Journal of medicinal chemistry, 1993Co-Authors: Paul W Baures, Lenora B. Cieslinski, Drake S Eggleston, Karl F Erhard, Theodore J Torphy, Siegfried B. ChristensenAbstract:Chiral HPLC resolution of the Phosphodiesterase IV (PDE IV) inhibitor rolipram (1) provided (-)-1, and this enantiomer was converted into its 1-(4-bromobenzyl) derIVatIVe, (+)-2. X-ray structural analysis of (+)-2 established the absolute configuration as R, which provides the first direct evidence for a previously assumed assignment of configuration. The crystal structure of (+)-2 and the PDE inhibitory actIVity of both enantiomers of 2 are discussed in the context of a previously proposed topological model.
Klaus Max Esser - One of the best experts on this subject based on the ideXlab platform.
-
characterization of camp dependent inhibition of lps induced tnfα production by rolipram a specific Phosphodiesterase IV pde IV inhibitor
International Journal of Immunopharmacology, 1994Co-Authors: Uma Prabhakar, Joan O'leary Bartus, David Lipshutz, M J Slivjak, Edward F Smith, John C Lee, Klaus Max EsserAbstract:Abstract Bacterial endotoxins (lipopolysaccharide or LPS) provoke shock and tissue injury by eliciting the release of toxic factors from reticuloendothelial cells. One of the principal endogenous factors involved in this process is tumor necrosis factor alpha (TNFα). In this study, inhibitors selectIVe for different classes of Phosphodiesterases (PDE), were examined for their effects on LPS-induced TNFα production by human monocytes. The selectIVe cAMP-PDE IV inhibitors, rolipram and RO-20-1724 were capable of inhibiting LPS-induced TNFα production by human monocytes in a concentration-dependent manner. Rolipram was used to examine further the cellular pharmacology of PDE IV inhibitors on cytokine production. The IC 50 for inhibition of LPS-induced TNFα production by rolipram was 0.1 μM, whereas production of IL-1β or IL-6 was unaffected. Furthermore, rolipram was equally effectIVe in inhibiting TNFα production by a number of other stimuli. Inhibition of TNFα production by rolipram was associated with an elevation of intracellular cAMP, consistent with a mechanism involving Phosphodiesterase inhibition. Rolipram was efficacious in suppressing LPS-induced TNFα mRNA expression, and at the protein level was also actIVe when added to cultures post-stimulated with LPS. This indicates that rolipram may act at both the transcriptional and translational levels. Rolipram inhibited TNFα production in vIVo in a rat endotoxemia model. CollectIVely, these data suggest that the phototypic inhibitor of PDE IV isozyme, rolipram, can effectIVely and selectIVely inhibit LPS-induced TNFα production through elevation of intracellular cAMP.
-
Characterization of cAMP-dependent inhibition of LPS-induced TNFα production by rolipram, a specific Phosphodiesterase IV (PDE IV) inhibitor
International journal of immunopharmacology, 1994Co-Authors: Uma Prabhakar, Joan O'leary Bartus, David Lipshutz, M J Slivjak, Edward F Smith, John C Lee, Klaus Max EsserAbstract:Bacterial endotoxins (lipopolysaccharide or LPS) provoke shock and tissue injury by eliciting the release of toxic factors from reticuloendothelial cells. One of the principal endogenous factors involved in this process is tumor necrosis factor alpha (TNF alpha). In this study, inhibitors selectIVe for different classes of Phosphodiesterases (PDE), were examined for their effects on LPS-induced TNF alpha production by human monocytes. The selectIVe cAMP-PDE IV inhibitors, rolipram and RO-20-1724 were capable of inhibiting LPS-induced TNF alpha production by human monocytes in a concentration-dependent manner. Rolipram was used to examine further the cellular pharmacology of PDE IV inhibitors on cytokine production. The IC50 for inhibition of LPS-induced TNF alpha production by rolipram was 0.1 microM, whereas production of IL-1 beta or IL-6 was unaffected. Furthermore, rolipram was equally effectIVe in inhibiting TNF alpha production by a number of other stimuli. Inhibition of TNF alpha production by rolipram was associated with an elevation of intracellular cAMP, consistent with a mechanism involving Phosphodiesterase inhibition. Rolipram was efficacious in suppressing LPS-induced TNF alpha mRNA expression, and at the protein level was also actIVe when added to cultures post-stimulated with LPS. This indicates that rolipram may act at both the transcriptional and translational levels. Rolipram inhibited TNF alpha production in vIVo in a rat endotoxemia model. CollectIVely, these data suggest that the prototypic inhibitor of PDE IV isozyme, rolipram, can effectIVely and selectIVely inhibit LPS-induced TNF alpha production through elevation of intracellular cAMP.
Alpeshkumar K. Malde - One of the best experts on this subject based on the ideXlab platform.
-
3D-QSAR studies of indole derIVatIVes as Phosphodiesterase IV inhibitors
European Journal of Medicinal Chemistry, 2003Co-Authors: Asit K. Chakraborti, B. Gopalakrishnan, M. Elizabeth Sobhia, Alpeshkumar K. MaldeAbstract:The 3D-QSAR studies of some indole derIVatIVes as Phosphodiesterase (PDE) type IV inhibitors was performed by ComparatIVe Molecular Field Analysis (CoMFA) and ComparatIVe Molecular Similarity Indices Analysis (CoMSIA) methods to determine the factors required for the actIVity of these compounds. The global minimum energy conformer of the template molecule, 3 the most actIVe molecule of the series, was obtained by simulated annealing method and used to build the structures of the molecules in the dataset. The CoMFA model produced statistically significant results with cross-validated and conventional correlation coefficients of 0.494 and 0.986 respectIVely. The combination of steric, electrostatic and hydrophobic fields in CoMSIA gave the best results with cross-validated and conventional correlation coefficients of 0.541 and 0.967 respectIVely. The predictIVe ability of CoMFA and CoMSIA were determined using a test set of seven indole derIVatIVes gIVing predictIVe correlation coefficients of 0.56 and 0.59 respectIVely indicating good predictIVe power. Further, the robustness of the models was verified by bootstrapping analysis. Based upon the information derIVed from CoMFA and CoMSIA, we have identified some key features that may be used to design new indole derIVatIVes and predict their PDE IV affinities prior to synthesis.
-
ComparatIVe molecular field analysis (CoMFA) of phthalazine derIVatIVes as Phosphodiesterase IV inhibitors
Bioorganic & medicinal chemistry letters, 2003Co-Authors: Asit K. Chakraborti, B. Gopalakrishnan, M. Elizabeth Sobhia, Alpeshkumar K. MaldeAbstract:A comparatIVe molecular field analysis (CoMFA) of phthalazine class of Phosphodiesterase IV (PDE IV) inhibitors has been performed to correlate their chemical structures with their observed biological actIVity. A statistically valid model with good correlatIVe and predictIVe power is reported. The leave one out cross-validation study gave cross-validation r2cv of value 0.507 at six optimum components and conventional r2 of value 0.98. The predictIVe ability of the model was tested by predicting the seven molecules belonging to the test set gIVing predictIVe correlation coefficient of 0.59. This model is potentially helpful in the design of novel and more potent PDE IV inhibitors.
-
3D-QSAR studies on thieno[3,2-d]pyrimidines as Phosphodiesterase IV inhibitors.
Bioorganic & medicinal chemistry letters, 2003Co-Authors: Asit K. Chakraborti, B. Gopalakrishnan, M. Elizabeth Sobhia, Alpeshkumar K. MaldeAbstract:Cyclic nucleotide Phosphodiesterase IV (PDE IV) inhibitors find utility in asthma and Chronic ObstructIVe Pulmonary Disease (COPD) therapy. A series of 29 thieno[3,2-d]pyrimidines with affinity for PDE IV was subjected to three dimensional quantitatIVe structure actIVity relationship (3D-QSAR) studies using comparatIVe molecular field analysis (CoMFA) and comparatIVe molecular similarity indices analysis (CoMSIA). Both CoMFA and CoMSIA provided statistically valid models with good correlatIVe and predictIVe power. The incorporation of hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields showed insignificant improvement in CoMSIA model. The 3D-QSAR models provide information for predicting the affinity of related compounds and designing more potent inhibitors.
Uma Prabhakar - One of the best experts on this subject based on the ideXlab platform.
-
characterization of camp dependent inhibition of lps induced tnfα production by rolipram a specific Phosphodiesterase IV pde IV inhibitor
International Journal of Immunopharmacology, 1994Co-Authors: Uma Prabhakar, Joan O'leary Bartus, David Lipshutz, M J Slivjak, Edward F Smith, John C Lee, Klaus Max EsserAbstract:Abstract Bacterial endotoxins (lipopolysaccharide or LPS) provoke shock and tissue injury by eliciting the release of toxic factors from reticuloendothelial cells. One of the principal endogenous factors involved in this process is tumor necrosis factor alpha (TNFα). In this study, inhibitors selectIVe for different classes of Phosphodiesterases (PDE), were examined for their effects on LPS-induced TNFα production by human monocytes. The selectIVe cAMP-PDE IV inhibitors, rolipram and RO-20-1724 were capable of inhibiting LPS-induced TNFα production by human monocytes in a concentration-dependent manner. Rolipram was used to examine further the cellular pharmacology of PDE IV inhibitors on cytokine production. The IC 50 for inhibition of LPS-induced TNFα production by rolipram was 0.1 μM, whereas production of IL-1β or IL-6 was unaffected. Furthermore, rolipram was equally effectIVe in inhibiting TNFα production by a number of other stimuli. Inhibition of TNFα production by rolipram was associated with an elevation of intracellular cAMP, consistent with a mechanism involving Phosphodiesterase inhibition. Rolipram was efficacious in suppressing LPS-induced TNFα mRNA expression, and at the protein level was also actIVe when added to cultures post-stimulated with LPS. This indicates that rolipram may act at both the transcriptional and translational levels. Rolipram inhibited TNFα production in vIVo in a rat endotoxemia model. CollectIVely, these data suggest that the phototypic inhibitor of PDE IV isozyme, rolipram, can effectIVely and selectIVely inhibit LPS-induced TNFα production through elevation of intracellular cAMP.
-
Characterization of cAMP-dependent inhibition of LPS-induced TNFα production by rolipram, a specific Phosphodiesterase IV (PDE IV) inhibitor
International journal of immunopharmacology, 1994Co-Authors: Uma Prabhakar, Joan O'leary Bartus, David Lipshutz, M J Slivjak, Edward F Smith, John C Lee, Klaus Max EsserAbstract:Bacterial endotoxins (lipopolysaccharide or LPS) provoke shock and tissue injury by eliciting the release of toxic factors from reticuloendothelial cells. One of the principal endogenous factors involved in this process is tumor necrosis factor alpha (TNF alpha). In this study, inhibitors selectIVe for different classes of Phosphodiesterases (PDE), were examined for their effects on LPS-induced TNF alpha production by human monocytes. The selectIVe cAMP-PDE IV inhibitors, rolipram and RO-20-1724 were capable of inhibiting LPS-induced TNF alpha production by human monocytes in a concentration-dependent manner. Rolipram was used to examine further the cellular pharmacology of PDE IV inhibitors on cytokine production. The IC50 for inhibition of LPS-induced TNF alpha production by rolipram was 0.1 microM, whereas production of IL-1 beta or IL-6 was unaffected. Furthermore, rolipram was equally effectIVe in inhibiting TNF alpha production by a number of other stimuli. Inhibition of TNF alpha production by rolipram was associated with an elevation of intracellular cAMP, consistent with a mechanism involving Phosphodiesterase inhibition. Rolipram was efficacious in suppressing LPS-induced TNF alpha mRNA expression, and at the protein level was also actIVe when added to cultures post-stimulated with LPS. This indicates that rolipram may act at both the transcriptional and translational levels. Rolipram inhibited TNF alpha production in vIVo in a rat endotoxemia model. CollectIVely, these data suggest that the prototypic inhibitor of PDE IV isozyme, rolipram, can effectIVely and selectIVely inhibit LPS-induced TNF alpha production through elevation of intracellular cAMP.
Paul W Baures - One of the best experts on this subject based on the ideXlab platform.
-
the crystal structure absolute configuration and Phosphodiesterase inhibitory actIVity of 1 4 bromobenzyl 4 3 cyclopentyloxy 4 methoxyphenyl pyrrolidin 2 one
Journal of Medicinal Chemistry, 1993Co-Authors: Paul W Baures, Lenora B. Cieslinski, Drake S Eggleston, Karl F Erhard, Theodore J Torphy, Siegfried B. ChristensenAbstract:Chiral HPLC resolution of the Phosphodiesterase IV (PDE IV) inhibitor rolipram (1) provided (-)-1, and this enantiomer was converted into its 1-(4-bromobenzyl) derIVatIVe, (+)-2. X-ray structural analysis of (+)-2 established the absolute configuration as R, which provides the first direct evidence for a previously assumed assignment of configuration. The crystal structure of (+)-2 and the PDE inhibitory actIVity of both enantiomers of 2 are discussed in the context of a previously proposed topological model.
-
The crystal structure, absolute configuration, and Phosphodiesterase inhibitory actIVity of (+)-1-(4-bromobenzyl)-4-(3-(cyclopentyloxy)- 4-methoxyphenyl)-pyrrolidin-2-one.
Journal of medicinal chemistry, 1993Co-Authors: Paul W Baures, Lenora B. Cieslinski, Drake S Eggleston, Karl F Erhard, Theodore J Torphy, Siegfried B. ChristensenAbstract:Chiral HPLC resolution of the Phosphodiesterase IV (PDE IV) inhibitor rolipram (1) provided (-)-1, and this enantiomer was converted into its 1-(4-bromobenzyl) derIVatIVe, (+)-2. X-ray structural analysis of (+)-2 established the absolute configuration as R, which provides the first direct evidence for a previously assumed assignment of configuration. The crystal structure of (+)-2 and the PDE inhibitory actIVity of both enantiomers of 2 are discussed in the context of a previously proposed topological model.