The Experts below are selected from a list of 204 Experts worldwide ranked by ideXlab platform
Kazuhisa Furuhama - One of the best experts on this subject based on the ideXlab platform.
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protective effect of ds 4574 a Peptidoleukotriene receptor antagonist against endotoxin induced intestinal injury in rats
European Journal of Pharmacology, 1995Co-Authors: Yoshiaki Tabuchi, Kazuhisa FuruhamaAbstract:Abstract We evaluated the protective effect of DS-4574 (6-(2-cyclohexylethyl)-[1,3,4]thiadiazolo[3,2- a ]-1,2,3-triazolo[4,5- d ]pyrimidin-9(3 H )-one), a Peptidoleukotriene receptor antagonist, against intestinal mucosal injury evoked by endotoxin in rats by exploring changes in hematocrit and plasma leakage along with morphological features. Treatment with Escherichia coli endotoxin (5 mg/kg i.v.) alone elicited hemoconcentration, vasocongestion and a marked mucosal necrosis. DS-4574 (10–50 mg/kg) effectively prevented these changes on either oral or intraduodenal administration. These results demonstrate that Peptidoleukotrienes may be key mediators in the intestinal injury induced by endotoxin in rats.
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Ebselen, a seleno-organic compound, protects against ethanol-induced murine gastric mucosal injury in both in vivo and in vitro systems
European Journal of Pharmacology, 1995Co-Authors: Yoshiaki Tabuchi, Norifumi Sugiyama, Tadashi Horiuchi, Mitsuru Furusawa, Kazuhisa FuruhamaAbstract:Abstract The inhibitory effect of the seleno-organic compound ebselen on ethanol-induced murine gastric mucosal injury was examined. In an in vivo study, absolute ethanol (50 μl/mouse, oral) produced marked gastric mucosal necrosis along with hemorrhage or edema and elevations in both lipid peroxide and Peptidoleukotriene levels in the fundic mucosa. Pretreatment with ebselen (30 and 100 mg/kg, oral) significantly prevented this gastric mucosal injury and, further, remarkably decreased the elevated lipid peroxide and Peptidoleukotriene levels. In an in vitro study using a murine gastric surface mucous cell line GSM06, exposure to ethanol concentration dependently elicited cell damage (7.5–17.5% ethanol) and an increase in lipid peroxides without alterations in Peptidoleukotrienes (15% ethanol). Addition of ebselen (10 and 100 μM) to this system (15% ethanol) significantly inhibited the cell damage and completely prevented the increase in lipid peroxide level. These results indicate that ebselen protects against murine gastric mucosal injury both in vivo and in vitro, and that this protection may be related at least in part to its inhibitory action on lipid peroxides.
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Inhibitory effect of DS-4574, a mast cell stabilizer with Peptidoleukotriene receptor antagonism, on gastric acid secretion in rats
European Journal of Pharmacology, 1994Co-Authors: Yoshiaki Tabuchi, Kazuhisa FuruhamaAbstract:We examined the inhibitory effect of DS-4574 (6-(2-cyclohexylethyl)[1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d] py pyrimidin-9(3H)-one), a mast cell stabilizer with Peptidoleukotriene receptor antagonism, on gastric acid secretion stimulated by several secretagogues in rats. In anesthetized rats with acute gastric fistulas, DS-4574 (50 mg/kg, intraduodenal) significantly inhibited gastric acid secretion induced by both carbachol (50 μg/kg, s.c.) and pentagastrin (75 μg/kg, s.c.), but not by histamine (2.5 mg/kg, s.c.). In unanesthetized pylorus-ligated rats, DS-4574 (10 and 25 mg/kg, intraduodenal) markedly suppressed increases in gastric acid output and histamine leakage into the gastric juice produced by carbachol (0.1 mg/kg, s.c.) or pentagastrin (1 mg/kg, s.c.). When the relationship between acid output and histamine leakage elicited by carbachol and pentagastrin was assessed, there was a close correlation (r = 0.84) that was highly significant (P < 0.01). In the in vitro study with rat gastric tissues, DS-4574 (10−7–10−5 M) had no effect on the K+-dependent ATPase activity or on aminopyrine uptake into mucosal preparations containing parietal cells stimulated by carbachol (10−5 M), histamine (10−4 M), or dibutyryl-cyclic AMP (10−3 M). These results suggest that the effect of DS-4574 may be mediated by inhibition of endogenous histamine from histamine-storing cells in the stomach.
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inhibitory effect of ds 4574 a Peptidoleukotriene antagonist with mast cell stabilizing action on compound 48 80 induced gastric mucosal lesions in rats
Inflammation Research, 1994Co-Authors: Yoshiaki Tabuchi, K. Kawarabayashi, Kazuhisa FuruhamaAbstract:We evaluated the inhibitory effect of DS-4574, a Peptidoleukotriene antagonist with mast cell stabilizing action, on rat gastric mucosal lesions induced by compound 48/80 (C48/80: a mast cell degranulator), in comparison with those of disodium cromoglycate (DSCG: a mast cell stabilizer), LY171883 (a Peptidoleukotriene antagonist) and cimetidine (a histamine H2 receptor antagonist). Subcutaneous administration of C48/80 (1 mg/kg) once daily for four consecutive days produced extensive gastric lesions in the fundic mucosa. DS-4574 (20, 50 and 100 mg/kg/day, oral) and DSCG (200 mg/kg/day, intraperitoneal) treatment markedly inhibited formation of these mucosal lesions, but LY171883 (100 and 200 mg/kg/day, oral) and cimetidine (400 mg/kg/day, oral) treatment did not. Moreover, DS-4574 and DSCG significantly suppressed both hyperhistaminemia and histamine release from rat peritoneal mast cells induced by C48/80. These results indicate that the inhibitory effect of DS-4574 on gastric lesions induced by C48/80 may be related to its mast cell stabilizing action, but to neither its antisecretory nor its Peptidoleukotriene antagonistic activity.
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Protective effect of DS-4574 on gastric mucosal injury induced by acidified ethanol in rats.
European Journal of Pharmacology, 1993Co-Authors: Yoshiaki Tabuchi, K. Kawarabayashi, Tohru Komada, Kazuhisa FuruhamaAbstract:Abstract We compared the protective effect of DS-4574, a Peptidoleukotriene receptor antagonist with mast cell stabilizing action, on rat gastric mucosal injury induced by acidified ethanol to that of LY171883, a selective Peptidoleukotriene receptor antagonist. Oral treatment with DS-4574 (1–10 mg/kg) or LY171883 (100 and 300 mg/kg) markedly suppressed this mucosal necrosis. Moreoer, DS-4574 (10 mg/kg) significantly inhibited both mucosal edema and degranulation of mucosal mast cells. LY171883 (300 mg/kg) protected only from mucosal edema, but not degranulation of mucosal mast cells. These results suggest that DS-4574 possesses protective actions against gastric injury including the reduction of degranulation of mucosal mast cells, which are different from those of LY171883.
Ted K Chen - One of the best experts on this subject based on the ideXlab platform.
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direct high performance liquid chromatographic separation of an enantiomeric Peptidoleukotriene antagonist and its homologues
Journal of Chromatography A, 1994Co-Authors: Ted K Chen, Robert J MillsAbstract:Abstract Racemic SK&F 106203 and its homologues can be directly separated on Chiralcel OD, Chiralpak AD and AS columns. The corresponding dimethyl esters, however, can only be resolved on the Chiralcel OD column. Hydrogen bonding between the carboxylic acid proton of the analyte and the chiral stationary phase appears critical for chiral recognition on Chiralpak AS column for these carboxylic acid compounds. Substitution at the 2 position of the parent phenyl ring appeared to aid chiral separation on Chiralcel OD column. The elution order of SK&F 106203 obtained on a Chiral OD column can also be reversed on a Chiralpak AS column.
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direct high performance liquid chromatographic separation of enantiomeric Peptidoleukotriene antagonists
Journal of Chromatography A, 1992Co-Authors: Ted K Chen, Karl F Erhard, Drake S Eggleston, May Y K HoAbstract:Abstract Enantiomeric Peptidoleukotriene antagonists, SK&F R -106203 and SK&F S -106203 can be effectively separated on a cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phase. The utility of this chiral high-performance liquid chromatographic method in assigning absolute stereochemistry to SK&F S -106203- Z 2 , a non-crystalline amorphous compound which is not amenable to single crystal X-ray analysis, is demonstrated by correlation with the absolute configuration determined crystallographically for a second salt form.
Yoshiaki Tabuchi - One of the best experts on this subject based on the ideXlab platform.
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protective effect of ds 4574 a Peptidoleukotriene receptor antagonist against endotoxin induced intestinal injury in rats
European Journal of Pharmacology, 1995Co-Authors: Yoshiaki Tabuchi, Kazuhisa FuruhamaAbstract:Abstract We evaluated the protective effect of DS-4574 (6-(2-cyclohexylethyl)-[1,3,4]thiadiazolo[3,2- a ]-1,2,3-triazolo[4,5- d ]pyrimidin-9(3 H )-one), a Peptidoleukotriene receptor antagonist, against intestinal mucosal injury evoked by endotoxin in rats by exploring changes in hematocrit and plasma leakage along with morphological features. Treatment with Escherichia coli endotoxin (5 mg/kg i.v.) alone elicited hemoconcentration, vasocongestion and a marked mucosal necrosis. DS-4574 (10–50 mg/kg) effectively prevented these changes on either oral or intraduodenal administration. These results demonstrate that Peptidoleukotrienes may be key mediators in the intestinal injury induced by endotoxin in rats.
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Ebselen, a seleno-organic compound, protects against ethanol-induced murine gastric mucosal injury in both in vivo and in vitro systems
European Journal of Pharmacology, 1995Co-Authors: Yoshiaki Tabuchi, Norifumi Sugiyama, Tadashi Horiuchi, Mitsuru Furusawa, Kazuhisa FuruhamaAbstract:Abstract The inhibitory effect of the seleno-organic compound ebselen on ethanol-induced murine gastric mucosal injury was examined. In an in vivo study, absolute ethanol (50 μl/mouse, oral) produced marked gastric mucosal necrosis along with hemorrhage or edema and elevations in both lipid peroxide and Peptidoleukotriene levels in the fundic mucosa. Pretreatment with ebselen (30 and 100 mg/kg, oral) significantly prevented this gastric mucosal injury and, further, remarkably decreased the elevated lipid peroxide and Peptidoleukotriene levels. In an in vitro study using a murine gastric surface mucous cell line GSM06, exposure to ethanol concentration dependently elicited cell damage (7.5–17.5% ethanol) and an increase in lipid peroxides without alterations in Peptidoleukotrienes (15% ethanol). Addition of ebselen (10 and 100 μM) to this system (15% ethanol) significantly inhibited the cell damage and completely prevented the increase in lipid peroxide level. These results indicate that ebselen protects against murine gastric mucosal injury both in vivo and in vitro, and that this protection may be related at least in part to its inhibitory action on lipid peroxides.
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Inhibitory effect of DS-4574, a mast cell stabilizer with Peptidoleukotriene receptor antagonism, on gastric acid secretion in rats
European Journal of Pharmacology, 1994Co-Authors: Yoshiaki Tabuchi, Kazuhisa FuruhamaAbstract:We examined the inhibitory effect of DS-4574 (6-(2-cyclohexylethyl)[1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d] py pyrimidin-9(3H)-one), a mast cell stabilizer with Peptidoleukotriene receptor antagonism, on gastric acid secretion stimulated by several secretagogues in rats. In anesthetized rats with acute gastric fistulas, DS-4574 (50 mg/kg, intraduodenal) significantly inhibited gastric acid secretion induced by both carbachol (50 μg/kg, s.c.) and pentagastrin (75 μg/kg, s.c.), but not by histamine (2.5 mg/kg, s.c.). In unanesthetized pylorus-ligated rats, DS-4574 (10 and 25 mg/kg, intraduodenal) markedly suppressed increases in gastric acid output and histamine leakage into the gastric juice produced by carbachol (0.1 mg/kg, s.c.) or pentagastrin (1 mg/kg, s.c.). When the relationship between acid output and histamine leakage elicited by carbachol and pentagastrin was assessed, there was a close correlation (r = 0.84) that was highly significant (P < 0.01). In the in vitro study with rat gastric tissues, DS-4574 (10−7–10−5 M) had no effect on the K+-dependent ATPase activity or on aminopyrine uptake into mucosal preparations containing parietal cells stimulated by carbachol (10−5 M), histamine (10−4 M), or dibutyryl-cyclic AMP (10−3 M). These results suggest that the effect of DS-4574 may be mediated by inhibition of endogenous histamine from histamine-storing cells in the stomach.
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inhibitory effect of ds 4574 a Peptidoleukotriene antagonist with mast cell stabilizing action on compound 48 80 induced gastric mucosal lesions in rats
Inflammation Research, 1994Co-Authors: Yoshiaki Tabuchi, K. Kawarabayashi, Kazuhisa FuruhamaAbstract:We evaluated the inhibitory effect of DS-4574, a Peptidoleukotriene antagonist with mast cell stabilizing action, on rat gastric mucosal lesions induced by compound 48/80 (C48/80: a mast cell degranulator), in comparison with those of disodium cromoglycate (DSCG: a mast cell stabilizer), LY171883 (a Peptidoleukotriene antagonist) and cimetidine (a histamine H2 receptor antagonist). Subcutaneous administration of C48/80 (1 mg/kg) once daily for four consecutive days produced extensive gastric lesions in the fundic mucosa. DS-4574 (20, 50 and 100 mg/kg/day, oral) and DSCG (200 mg/kg/day, intraperitoneal) treatment markedly inhibited formation of these mucosal lesions, but LY171883 (100 and 200 mg/kg/day, oral) and cimetidine (400 mg/kg/day, oral) treatment did not. Moreover, DS-4574 and DSCG significantly suppressed both hyperhistaminemia and histamine release from rat peritoneal mast cells induced by C48/80. These results indicate that the inhibitory effect of DS-4574 on gastric lesions induced by C48/80 may be related to its mast cell stabilizing action, but to neither its antisecretory nor its Peptidoleukotriene antagonistic activity.
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Protective effect of DS-4574 on gastric mucosal injury induced by acidified ethanol in rats.
European Journal of Pharmacology, 1993Co-Authors: Yoshiaki Tabuchi, K. Kawarabayashi, Tohru Komada, Kazuhisa FuruhamaAbstract:Abstract We compared the protective effect of DS-4574, a Peptidoleukotriene receptor antagonist with mast cell stabilizing action, on rat gastric mucosal injury induced by acidified ethanol to that of LY171883, a selective Peptidoleukotriene receptor antagonist. Oral treatment with DS-4574 (1–10 mg/kg) or LY171883 (100 and 300 mg/kg) markedly suppressed this mucosal necrosis. Moreoer, DS-4574 (10 mg/kg) significantly inhibited both mucosal edema and degranulation of mucosal mast cells. LY171883 (300 mg/kg) protected only from mucosal edema, but not degranulation of mucosal mast cells. These results suggest that DS-4574 possesses protective actions against gastric injury including the reduction of degranulation of mucosal mast cells, which are different from those of LY171883.
May Y K Ho - One of the best experts on this subject based on the ideXlab platform.
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direct high performance liquid chromatographic separation of enantiomeric Peptidoleukotriene antagonists
Journal of Chromatography A, 1992Co-Authors: Ted K Chen, Karl F Erhard, Drake S Eggleston, May Y K HoAbstract:Abstract Enantiomeric Peptidoleukotriene antagonists, SK&F R -106203 and SK&F S -106203 can be effectively separated on a cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phase. The utility of this chiral high-performance liquid chromatographic method in assigning absolute stereochemistry to SK&F S -106203- Z 2 , a non-crystalline amorphous compound which is not amenable to single crystal X-ray analysis, is demonstrated by correlation with the absolute configuration determined crystallographically for a second salt form.
David W Snyder - One of the best experts on this subject based on the ideXlab platform.
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1 3 6 trisubstituted indoles as Peptidoleukotriene antagonists benefits of a second polar pyrrole substituent
Journal of Medicinal Chemistry, 1992Co-Authors: Frederick J. Brown, L A Cronk, David Aharony, David W SnyderAbstract:: 1,6-Substituted and 3,5-substituted indoles and indazoles containing acylamino and N-arylsulfonyl amide appendages are potent antagonists of the Peptidoleukotrienes LTD4 and LTE4. A compound from the 3,5-substituted indole series, N-[4-[[5-[[(cyclopentyloxy)carbonyl]amino]-1-methylindol- 3-yl]methyl]-3-methoxybenzoyl]-2-methyl-benzenesulfonamide (ICI 204,219), is undergoing clinical evaluation for asthma. Two new elements of structural diversity were introduced to this series of antagonists. An investigation of pyrrole substituents in the 1,6-substituted indoles demonstrated that substitution at C-2 was detrimental to biological activity, but the incorporation of hydrophilic groups at C-3 was beneficial. The introduction of a propionamide moiety at C-3 enhanced activity by 1 order of magnitude; N-[4-[[6-(cyclopentylacetamido)-3-[2-(N- methylcarbamoyl)ethyl]indol-1-yl]methyl]-3-methoxy- benzoyl]benzenesulfonamide (15c) has a pKB of 10.7 at the LTD4 receptor on guinea pig trachea. Modifications of the acylamino portion of the disubstituted antagonists demonstrated that a transposition of the amide CO and NH atoms was viable. N-Cyclopentylmethyl amides in both the 1,6- and 3,5-disubstituted indole series were 1 order of magnitude less potent than the corresponding cyclopentylacetamides. In both series this potency loss could be regained by the incorporation of a propionamide substituent at either C-3 or N-1, respectively. For example, N-[4-[[6-[N-(cyclopentylmethyl)carbamoyl]-3-[2-(pyrrolidin-1 - methylbenzenesulfonamide (39c) has a pKB of 9.5.
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evolution of a series of Peptidoleukotriene antagonists synthesis and structure activity relationships of 1 3 5 substituted indoles and indazoles
Journal of Medicinal Chemistry, 1990Co-Authors: Victor Giulio Matassa, Thomas P. Maduskuie, H. S. Shapiro, David Aharony, David W Snyder, Barrie Hesp, Robert D Krell, Richard A KeithAbstract:: 1,3,5-Substituted indoles and indazoles have been studied as receptor antagonists of the Peptidoleukotrienes. The best of these compounds generally had a methyl group at the N1 position, a [(cyclopentyloxy)carbonyl]amino or 2-cyclopentylacetamido or N'-cyclopentylureido group at the C-5 position, and an arylsulfonyl amide group as part of the acidic chain at the C-3 position of the ring. Such compounds had in vitro dissociation constants (KB) in the range 10(-9) - 10(-11) M on guinea pig trachea against LTE4 as agonist and inhibition constants (Ki) less than or equal to 10(-9) M on guinea pig parenchymal membranes against [3H]LTD4. A number of compounds were orally effective at doses less than or equal to 1 mg/kg in blocking LTD4-induced "dyspnea" in guinea pigs. Compound 45 [N-[4-[[5-[[(cyclopentyloxy)carbonyl]-amino]-1-methylindol-3- yl]methyl]-3-methoxybenzoyl]-2-methylbenzenesulfonamide, ICI 204,219; pKB = 9.67 +/- 0.13, Ki = 0.3 +/- 0.03 nM, po ED50 = 0.3 mg/kg] is currently under clinical investigation for asthma. In the indole series, certain alkylsulfonyl amides possessing a 3-cyanobenzyl substituent at the N-1 position (60, 61) were produced that had KB less than or equal to 10(-9) M on guinea pig trachea.
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Evolution of a series of Peptidoleukotriene antagonists : synthesis and structure/activity relationships of 1,3,5-substituted indoles and indazoles
Journal of Medicinal Chemistry, 1990Co-Authors: Victor Giulio Matassa, Thomas P. Maduskuie, H. S. Shapiro, David W Snyder, Barrie Hesp, Robert D Krell, D. Aharony, Richard A KeithAbstract:: 1,3,5-Substituted indoles and indazoles have been studied as receptor antagonists of the Peptidoleukotrienes. The best of these compounds generally had a methyl group at the N1 position, a [(cyclopentyloxy)carbonyl]amino or 2-cyclopentylacetamido or N'-cyclopentylureido group at the C-5 position, and an arylsulfonyl amide group as part of the acidic chain at the C-3 position of the ring. Such compounds had in vitro dissociation constants (KB) in the range 10(-9) - 10(-11) M on guinea pig trachea against LTE4 as agonist and inhibition constants (Ki) less than or equal to 10(-9) M on guinea pig parenchymal membranes against [3H]LTD4. A number of compounds were orally effective at doses less than or equal to 1 mg/kg in blocking LTD4-induced "dyspnea" in guinea pigs. Compound 45 [N-[4-[[5-[[(cyclopentyloxy)carbonyl]-amino]-1-methylindol-3- yl]methyl]-3-methoxybenzoyl]-2-methylbenzenesulfonamide, ICI 204,219; pKB = 9.67 +/- 0.13, Ki = 0.3 +/- 0.03 nM, po ED50 = 0.3 mg/kg] is currently under clinical investigation for asthma. In the indole series, certain alkylsulfonyl amides possessing a 3-cyanobenzyl substituent at the N-1 position (60, 61) were produced that had KB less than or equal to 10(-9) M on guinea pig trachea.