properties of the reversible, K+-competitive inhibitor of the gastric H+/K+)-ATPase, SK&amp;F 97574. II. Pharmacological properties

Parsons, M. E.; Rushant, B.; Rasmussen, Tony C.; Leach, Colin A.; Ife, Robert J.; Postius, Stefan; Pope, Andrew J.

doi:10.1016/0006-2952(95)02021-7

Cited by 15 publications

(13 citation statements)

References 10 publications

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“…The ED 50 value of AU-461 was estimated to be 9.7 B 1.8 mg/kg p.o. (about 21 Ìmol/kg) which is comparable to that of SK&F 97574, another reversible inhibitor of gastric H + /K + ATPase [13].…”

Section: Discussionsupporting

confidence: 49%

“…Parsons et al reported that the action of SK&F 97574 remained for 8 h after the 1-hour i.v. infusion in the conscious Heidenhain pouch dog [13]. In contrast, omeprazole produced a very long duration of action, being detectable for 3-4 days after oral administration as it would be predicted for an irreversible inactivator of gastric H + /K + ATPase [14].…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological Properties of the Gastric H+/K+ ATPase Inhibitor, AU-461

Cheon

Kim

et al. 2000

Pharmacology

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AU-461 (1-(2-methyl-4-methoxyphenyl)-4-[(2-hydroxyethyl)amino]-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline) was tested for its ability to act as an anti-ulcer agent. AU-461 inhibited gastric H⁺/K⁺ ATPase activities with IC₅₀ values of 12.15 and 4.20 μmol/l for rabbit and pig enzymes, respectively. The inhibition was reversible, and competitive with respect to the activating cation K⁺. When AU-461 was examined for the in vivo antisecretory activity, we found that AU-461 reduced the histamine-stimulated acid secretion as well as the basal secretion in rat stomach. Duration of the antisecretory effect was about 6 h upon oral administration. AU-461 prevented dose-dependently the ulcer formation produced by either ethanol or NaOH. This protective effect was not altered by indomethacin pretreatment. In addition, the elevated plasma gastrin by the oral administration of AU-461 was returned to control by 12 h. Taken together, these results suggest that AU-461 could be developed as a new therapeutic agent for peptic ulcer disease.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Pharmacological Properties of the Gastric H+/K+ ATPase Inhibitor, AU-461

Cheon

Kim

et al. 2000

Pharmacology

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“…On restimulating 24 h later, little inhibitory effect could be observed, suggesting that the duration of action of 4, while longer than that of 3, was shorter than that of the irreversible (H+/K+)-ATPase inhibitor omeprazole. 19 The pifa of 4 was measured to be 6.86 at 25 °C. More detailed enzymological studies have shown that 4, like 3, is a freely reversible inhibitor of the gastric (H+/K+)-ATPase (if 0.46 µ ),20 suggesting that the pharmacodynamic difference between these compounds must arise as a consequence of their different pharmacokinetics.…”

Section: Resultsmentioning

confidence: 99%

“…In general the esters 17 were deprotected immediately without isolation. Oxidation to the aldehyde 19 allowed elaboration of this substituent (Scheme 4). Trimethylsulfoniumylide gave the epoxide 20, which could be ring-opened with amines, while an excess of methyl Grignard or vinyllithium gave the secondary alcohols 21 in modest yield.…”

Section: Chemistrymentioning

confidence: 99%

“…3-Butyryl-4-[(2-methylphenyl)amino]quinoline-8-carboxaldehyde (19). A stirred solution of oxalyl chloride (18.22 g, 144 mmol) in dry dichloromethane (180 mL) was cooled to -70 °C under nitrogen and a solution of dimethyl sulfoxide (13.08 g, 168 mmol) in dichloromethane (20 mL) added dropwise, keeping the temperature below -60 °C.…”

Section: Ethyl 2-butyryl-3-[[2-[[3-(ethoxycarbonyl)propyl]oxy]phenyl]...mentioning

confidence: 99%

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Reversible Inhibitors of the Gastric (H+/K+)-ATPase. 4. Identification of an Inhibitor with an Intermediate Duration of Action

Leach¹,

Brown²,

Ife³

et al. 1995

J. Med. Chem.

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3-Acyl-4-(arylamino)quinolines were previously identified as gastric (H+/K+)-ATPase inhibitors, and clinical efficacy has been demonstrated for compound 3 (SK&F 96067). In the present study the further structure-activity relationship of this series is developed. Only a limited range of substituents are tolerated on the N-aryl ring or the 6- and 7-positions of the quinoline, and although hydroxylated derivatives were identified possessing markedly greater affinity for the enzyme, none of these proved to have adequate potency after oral dosing. In contrast, the 8-position of the quinoline ring proved suitable for a wide variety of substituents, allowing modification of physicochemical properties while retaining primary activity. This led to the identification of compound 4 (SK&F 97574), which combines good oral potency with a somewhat longer duration of action than 3 (though much shorter than covalent inhibitors such as omeprazole). This compound was selected for further development and evaluation in man.

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Metabolism Pharmacology

Herling¹

2006

Drug Discovery and Evaluation

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properties of the reversible, K+-competitive inhibitor of the gastric H+/K+)-ATPase, SK&F 97574. II. Pharmacological properties

Cited by 15 publications

References 10 publications

Pharmacological Properties of the Gastric H<sup>+</sup>/K<sup>+</sup> ATPase Inhibitor, AU-461

Pharmacological Properties of the Gastric H<sup>+</sup>/K<sup>+</sup> ATPase Inhibitor, AU-461

Reversible Inhibitors of the Gastric (H+/K+)-ATPase. 4. Identification of an Inhibitor with an Intermediate Duration of Action

Metabolism Pharmacology

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