Tetrahydrochromenoimidazoles as potassium-competitive acid blockers (P-CABs): structure-activity relationship of their antisecretory properties and their affinity toward the hERG channel.

Potassium-competitive acid blockers (P-CABs) constitute a new therapeutic option for the treatment of acid-related diseases that are widespread and constitute a significant economical burden. Enantiomerically pure tetrahydrochromenoimidazoles were prepared using the readily available candidate 4 (BYK 405879) as starting material or the Noyori asymmetric reduction of ketones as key reaction. A comprehensive SAR regarding the influence of the 5-carboxamide and the 8-aryl residue on in vitro activity, acid-suppression in the Ghosh Schild rat, and affinity toward the hERG channel was established.

Soraprazan: setting new standards in inhibition of gastric acid secretion.

After treatment of millions of patients suffering from gastroesophageal reflux disease (GERD) and other acid-related ailments with proton pump inhibitors, there are still unmet medical needs such as rapid and reliable pain relief, especially for nocturnal acid breakthrough. In this work, we introduce and characterize the biochemistry and pharmacology of the potassium-competitive acid blocker (P-CAB) soraprazan, a novel, reversible, and fast-acting inhibitor of gastric H,K-ATPase. Inhibitory and binding properties of soraprazan were analyzed together with its mode of action, its selectivity, and its in vivo potency.

Toll-like receptors 2 and 4 do not contribute to clearance of Chlamydophila pneumoniae in mice, but are necessary for the release of monokines.

Activation of immune cells by Chlamydophila pneumoniae in vitro has been shown to be toll-like receptor (TLR2)-dependent, but TLR4 is also involved to a minor extent. To investigate the role of TLR2 and TLR4 in vivo, a murine model of C. pneumoniae infection was established.

Mutations of the Helicobacter pylori genes rdxA and pbp1 cause resistance against metronidazole and amoxicillin.

To investigate amoxicillin and metronidazole resistance of Helicobacter pylori, we compared putative resistance genes between resistant strains obtained in vitro and their sensitive parent strain. All metronidazole-resistant strains had rdxA mutations, and an amoxicillin-resistant strain had pbp1 and pbp2 mutations. By transforming PCR products of these mutated genes into antibiotic-sensitive strains, we showed that rdxA null mutations were sufficient for metronidazole resistance, while pbp1 mutations contributed to amoxicillin resistance of H.

Animal pharmacology of reversible antagonism of the gastric acid pump, compared to standard antisecretory principles.

To define the basic antisecretory profile of a potassium-competitive antagonism of the gastric acid pump relative to other classes of acid-inhibitory drugs, they were compared to each other against all three major stimuli of acid secretion. Pumaprazole is an imidazo-pyridine derivative that was used in this investigation as an example of reversibly binding acid pump antagonists (APAs). It differs from covalently binding proton pump inhibitors (PPIs), such as omeprazole, both with respect to chemical structure and mode of interaction with the gastric H(+)/K(+)-ATPase (i.

The Helicobacter felis ftsH gene encoding an ATP-dependent metalloprotease can replace the Escherichia coli homologue for growth and phage lambda lysogenization.

Cloning and sequencing of an approximately 6.0-kb chromosomal DNA fragment from Helicobacter felis revealed five complete open reading frames. The deduced amino acid sequence of one ORF exhibited sequence similarity to the FtsH protein, an ATP-dependent metalloprotease, from various bacterial species.

The role of internal urease in acid resistance of Helicobacter pylori.

Background & Aims: The relative role of internal urease for acid protection of Helicobacter pylori is unknown. The aim of this study was to determine the comparative importance of internal and external urease under acidic conditions.

Methods: The pH optimum and measured Michaelis constant for urea of external urease and urease in intact bacteria at different medium pH (pHout) were measured using 14CO2 release from 14C-urea.

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

SK&F 97574 [3-Butryl-4-(2-methylamino)-8-(2-hydroxyethoxy) quinoline] is a potent, reversible inhibitor of the gastric (H+/K+)-ATPase. In an anaesthetised lumen-perfused rat preparation, it inhibited pentagastrin-stimulated gastric acid secretion with intravenous and intraduodenal inhibitory ED50 values of 2.40 mumol/kg and 4.

Loss of circadian rhythm in luminal acidity of canine stomach by implantation of a gastric fistula.

One to four months after implantation of a gastric fistula, a circadian rhythm in gastric acidity could be demonstrated by use of the intragastric 24-hour pH-metry in dogs with the gastric fistula protruding on the left side of the upper abdomen. This circadian rhythm was found to be fully developed within 3 years, and it remained unchanged up to 5 years after implantation. It is characterized by a daytime intragastric median pH of about 2 and a nocturnal intragastric median pH of about 7.

Effect of acute and chronic acid suppression on plasma gastrin release in the rat.

The mechanisms by which administration of the H+,K(+)-ATPase inhibitor B 831-78 or intragastric perfusion with NaHCO3 induces plasma gastrin release were studied in the rat. Experiments were performed after a washout of residual intragastric contents in fasted animals provided with chronic gastric fistulae. Acute and chronic administration of B 831-78 elevated plasma gastrin dose-dependently up to 5-6 times above control levels, while the increase was only twofold with intragastric NaHCO3 infusion despite similar neutralization of gastric acidity.

The novel proton pump inhibitor pantoprazole elevates intragastric pH for a prolonged period when administered under conditions of stimulated gastric acid secretion in the gastric fistula dog.

The duration of intragastric pH-elevation upon administration of the novel H+K(+)-ATPase inhibitor pantoprazole and its pharmacodynamic interaction with H2 receptor blockade was assessed in the gastric fistula dog using the intragastric 24 hour pH-metry. Gastric acid secretion was stimulated by s.c.

BY 1023/SK&F 96022 INN pantoprazole, a novel gastric proton pump inhibitor, potently inhibits acid secretion but lacks relevant cytochrome P450 interactions.

The novel H+/K(+)-adenosine triphosphatase inhibitor (gastric proton pump inhibitor), BY 1023/SK&F 96022, was found to be more potent than omeprazole in some rat models and slightly less potent in a dog model. Overall, both compounds are of a similar potency and efficacy. BY 1023/SK&F 96022 exhibited a somewhat longer duration of the antisecretory action than omeprazole in the Ghosh-Schild rat.

Direct comparison between the ulcer-healing effects of two H(+)-K(+)-ATPase inhibitors, one M1-selective antimuscarinic and one H2 receptor antagonist in the rat.

A direct comparison of the ulcer-healing effects of two H(+)-K(+)-ATPase inhibitors (pantoprazole and omeprazole), one M1 antimuscarinic (telenzepine) and one H2 receptor antagonist (cimetidine) was performed in the rat. Gastric and duodenal ulcers were induced by local application of acetic acid and thereafter treated over 10 days by the test drugs. Overall and on a molar basis, ulcer healing was comparably accelerated by pantoprazole, omeprazole and telenzepine and less so by cimetidine.

Gastric prostaglandin E2 release induced by aluminium hydroxide and aluminium hydroxide-containing antacids in rats. Effect of low doses and citric acid.

Suspensions of aluminium hydroxide or a commercial antacid containing aluminium hydroxide (Trigastril) was instilled intragastrically in rats in doses comparable to high and low human therapeutic doses (aluminium hydroxide, 125 mg and 12.5 mg/kg, respectively). Corresponding experiments were carried out with 0.

Further evidence for gastroprotection induced by aluminium hydroxide in the rat.

The effect of aluminium hydroxide on the development of gastric mucosal lesions induced by microcirculatory disturbances was investigated in the rat. Aluminium hydroxide dose-dependently inhibited the serotonin-induced gastric damages. Carbachol give subcutaneously intensified the development both of ethanol-produced gastric erosions and of indometacin-induced lesions.

[Tetrahydroisoquinolines as components of H2-antagonists. 27. H2-antihistaminics].

In studies on structure-activity relationships of histamine H2-receptor antagonists, lamtidine-analogue derivatives of N-(3-hydroxyphenyl)guanidine and 5- and 7-hydroxy-tetrahydroisoquinoline were prepared and tested for their H2-antagonistic activity on the isolated guinea-pig atrium and on the histamine-stimulated acid secretion of the anaesthetized rat. A further aim of the investigations was to examine the influence of a lengthening of the side-chain as well as the substitution of the aminotriazole with other H2-antagonistic components, on the pharmacological data of the above-mentioned isoquinoline derivatives. All compounds made showed only little H2-antagonistic activity on the guinea-pig atrium.

Proliferation kinetics and metabolic features of in vitro grown Ehrlich ascites tumor cells in the presence of exogenous pyruvate.

The proliferation of in vitro grown Ehrlich ascites tumor cells is inhibited by pyruvate concentrations greater than 2 mM. In the presence of 4-5 mM pyruvate the growth is reduced to about 50%, in the presence of 20 mM to about 5-10%. Viability of the cells is not severely affected.

Evidence for an anaphylactic reaction-induced gastric acid secretion from the isolated stomach of the mouse.

Under in vitro circumstances, ovalbumin, administered serosally, caused a definite acid secretory response in the isolated whole stomach of sensitized mice. Acid secretion induced by challenge was inhibited by cimetidine or by pretreatment with disodium cromoglycate. It remained, however, unchanged by mepyramine or atropine.

Prostaglandin formation by isolated gastric parietal and nonparietal cells of the rat.

Rat gastric cells isolated by pronase and subdivided by Percoll into 3 fractions (F1, F2, F3) were used to study prostaglandin E2 (PGE2) formation and, as an indirect measure of parietal cell H+ production, [14C]-aminopyrine uptake. Cells that had not been fractionated, with 20 to 25% parietal cells, contained at 0 degree C 1.7 +/- 0.

[Isohistamine and homologs as components of H2-antagonists. 22. H2-antihistaminics].

Starting with isohistamines and their homologues or from appropriately hydrogenated imidazo[1,2-c]pyrimidines, imidazo[1,2-c] [1,3]diazepines and -diazocines, H2-antihistaminics with cyanoguanidine and 2-nitro-1,1-ethenediamine structure were prepared and tested for their H2-antagonistic activity on the isolated guinea-pig atrium and on the histamine-stimulated acid secretion of the anaesthetized rat. While the cyanoguanidines 3a-c,f were weaker in comparison to cimetidine, or inactive, 12a-e,g-l, 17 and 19 possessed markedly stronger activity, whereby the activity reaches a maximal effect at the rat stomach when cyanoguanidine and imidazole ring are connected with a three-membered chain. The activity of the 2-nitro-1,1-ethenediamines 15b,h,l exceed that of the comparable cyanoguanidines at both test models.

[C-2 basically substituted thiazoles with H2-antagonistic action. 21. H2-antihistaminics].

In studies on structure-activity relationships of histamine H2-receptor antagonists, C-2 basically substituted thiazoles were prepared and tested for their H2-antihistaminic activity on the isolated guinea-pig atrium and on the histamine stimulated acid secretion of the anaesthetized rat. As a basic substituent the dimethylaminomethyl group is especially suitable, while cyclic guanidines lead to lower H2-antagonistic activity.

Evidence for thimerosal induced cytoprotection on rat stomach.

Intragastrically administered thimerosal protects against ethanol induced ulceration with an ID50 of 1.6 mg/kg body weight. In contrast, intravenously administered thimerosal exhibits an ID50 of greater than 30 mg/kg.

The effect of different histamine H2-receptor antagonists on the gastric acid secretion of the isolated whole stomach of the mouse and on the heart rate of spontaneously beating atrium of the guinea-pig.

The effect of metiamide, cimetidine and 2-[2-[5-(dimethylaminomethyl)furan-2-ylmethylthio]ethylamino]- 5-(6-methylpyrid-3-ylmethyl)-pyrimidin-4-one (SK & F 93 479) was studied on the acid secretion of the isolated stomach of the mouse and on the heart rate of the right atrium of the guinea-pig. The order of potency of histamine H2-antagonists investigated was identical on atrium and stomach, however, the pA2 values obtained on acid secretion were approximately 10 times lower than those found on atrium.

[Synthesis and H2-antihistaminic effect of N,N'-bisheteroaryl N,N'-bisheteroaryl-substituted cyanoguanidines and 2-nitro-1,1-ethenediamines. 17. H2-antihistaminics].

In studies on structure-activity relationships of histamine H2-receptor antagonists, cyanoguanidines and 2-nitro-1,1-ethendiamines, which contain the heterocyclic rings of ranitidine and cimetidine twofold, were prepared and tested for their H2-antihistaminic activity on the isolated guinea-pig atrium and on the histamine stimulated acid secretion of the anaesthetized rat. While the N,N'-disubstituted keten-N,N-acetales 8 and 11 possess markedly stronger H2-antagonistic activity than Ranitidine, the analogously substituted cyanoguanidines 3b and 6 proved to be as effective as the reference substance. The substances 3a and 13, with unsubstituted C-5 position of one heterocyclus, showed lower potency.