Heidenhain Pouch Dogs Research Articles

KFP-H008 blocks gastric acid secretion through inhibiting H+-K+-ATPase

1-(5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (KFP-H008)，a novel and potent potassium-competitive acid blocker for the treatment of acid secretion related diseases, has not been reported previously. In this study, we demonstrated that KFP-H008 inhibits basal acid secretion, 2-deoxy-D-glucose- (2DG-) stimulated gastric acid secretion in rats. KFP-H008 blocked histamine-stimulated acid secretion in rats and heidenhain pouch dogs and reversed acid output in isolated gastric perfusion under histamine stimulation. In all the animal experiments, KFP-H008 exerted a more effective, potent and longer-lasting inhibitory action in comparison with lansoprazole, a proton pump inhibitor (PPI) commonly used in clinic. KFP-H008 inhibited H+-K+-ATPase activity both at pH 6.5 and pH 7.5, and was unaffected by pH. The inhibitory action was reversible and was achieved in a K+-competitive manner. Furthermore, KFP-H008 did not affect Na+-K+-ATPase activity, thus exhibiting high selectivity, which is different from PPIs. In all, KFP-H008, a novel potassium-competitive acid blocker, may provide new option for the patients with acid-related diseases and provide longer-lasting inhibitory action than drugs commonly used in clinical treatment.

Tu1830 Predictors of Slow Healing of Reflux Esophagitis With Potent Acid Suppression

Introduction: Proton pump inhibitors (PPIs) are now widely used for the treatment of acidrelated diseases, such as peptic ulcer and gastroesophageal reflux disease (GERD). PPIs which are weak-base prodrugs are activated in an acidic condition and only inhibit H+/K+ATPase that has already been activated. Therefore, the effect of PPIs on acid-related diseases is slow onset and their maximum efficacy can be achieved after several days of dosing, leading to unmet medical needs such as nocturnal acid breakthrough and unsatisfied symptom relief. Methods: We investigated the pharmacological profiles of YH4808, a novel potent, highly selective K+-competitive acid blocker (P-CAB), in terms of hog gastric H+/K+-ATPase activity, gastric acid secretion, and acute gastroesophageal lesions in animal models, in comparison with esomeprazole. In addition, a quantitative whole body autoradiography (QWBA) study was performed with [14C]YH4808 (10 mg/kg) in rats to characterize tissue distribution. Results: YH4808 inhibited H+/K+-ATPase activity in a concentration-dependent manner, with an IC50 value of 3.4 nM which is more potent than that of esomeprazole. The inhibitory mechanism of YH4808 on H+/K+-ATPase was a competitive antagonism to the K+-binding site of H+/K+-ATPase, and it was also a reversible inhibition. In a selectivity assay, YH4808 showed 3,000-fold greater selectivity against Na+/K+-ATPase. In pylorus-ligated rats, oral administration of YH4808 inhibited basal acid secretion in a dose-dependent manner with the ID50 value of 1.1 mg/kg. Anti-secretory activity of YH4808 against histamine-stimulated acid secretion in rats after IV injection (ID50=0.1 mg/kg) was stronger than that of esomeprazole (ID50=0.9 mg/kg). In Heidenhain pouch dogs, IV administration of YH4808 inhibited histamine-stimulated acid secretion in a dose-dependent manner with almost complete inhibition at the dose of 0.6 mg/kg. In a reflux esophagitis model, intraduodenal administration of YH4808 prevented esophageal lesions by 30, 82 and 91% at a dose of 1, 3, and 10 mg/kg, respectively while esomeprazole reduced the lesion by 47% at 10 mg/kg. A QWBA study in rats showed YH4808 accumulated and was retained in the gastric tissue for more than 24h after oral administration. Conclusion: YH4808, a novel selective P-CAB exerted a potent, longer-lasting anti-secretory efficacy through high accumulation in the gastric tissue, which translated into the more effective inhibition of reflux esophagitis than esomeprazole. These findings indicate that YH4808 can provide significant clinical benefits to patients with acid-related diseases.

Tu1827 Yh4808, a Potent, Highly Selective K+-Competitive Acid Blocker, Suppressed Rat Acute Reflux Esophagitis More Effectively Than Esomeprazole

Introduction: Proton pump inhibitors (PPIs) are now widely used for the treatment of acidrelated diseases, such as peptic ulcer and gastroesophageal reflux disease (GERD). PPIs which are weak-base prodrugs are activated in an acidic condition and only inhibit H+/K+ATPase that has already been activated. Therefore, the effect of PPIs on acid-related diseases is slow onset and their maximum efficacy can be achieved after several days of dosing, leading to unmet medical needs such as nocturnal acid breakthrough and unsatisfied symptom relief. Methods: We investigated the pharmacological profiles of YH4808, a novel potent, highly selective K+-competitive acid blocker (P-CAB), in terms of hog gastric H+/K+-ATPase activity, gastric acid secretion, and acute gastroesophageal lesions in animal models, in comparison with esomeprazole. In addition, a quantitative whole body autoradiography (QWBA) study was performed with [14C]YH4808 (10 mg/kg) in rats to characterize tissue distribution. Results: YH4808 inhibited H+/K+-ATPase activity in a concentration-dependent manner, with an IC50 value of 3.4 nM which is more potent than that of esomeprazole. The inhibitory mechanism of YH4808 on H+/K+-ATPase was a competitive antagonism to the K+-binding site of H+/K+-ATPase, and it was also a reversible inhibition. In a selectivity assay, YH4808 showed 3,000-fold greater selectivity against Na+/K+-ATPase. In pylorus-ligated rats, oral administration of YH4808 inhibited basal acid secretion in a dose-dependent manner with the ID50 value of 1.1 mg/kg. Anti-secretory activity of YH4808 against histamine-stimulated acid secretion in rats after IV injection (ID50=0.1 mg/kg) was stronger than that of esomeprazole (ID50=0.9 mg/kg). In Heidenhain pouch dogs, IV administration of YH4808 inhibited histamine-stimulated acid secretion in a dose-dependent manner with almost complete inhibition at the dose of 0.6 mg/kg. In a reflux esophagitis model, intraduodenal administration of YH4808 prevented esophageal lesions by 30, 82 and 91% at a dose of 1, 3, and 10 mg/kg, respectively while esomeprazole reduced the lesion by 47% at 10 mg/kg. A QWBA study in rats showed YH4808 accumulated and was retained in the gastric tissue for more than 24h after oral administration. Conclusion: YH4808, a novel selective P-CAB exerted a potent, longer-lasting anti-secretory efficacy through high accumulation in the gastric tissue, which translated into the more effective inhibition of reflux esophagitis than esomeprazole. These findings indicate that YH4808 can provide significant clinical benefits to patients with acid-related diseases.

Tu1828 Impact of Regurgitation on Health-Related Quality of Life (HRQoL) in Gastroesophageal Reflux Disease (GERD)

Introduction: Proton pump inhibitors (PPIs) are now widely used for the treatment of acidrelated diseases, such as peptic ulcer and gastroesophageal reflux disease (GERD). PPIs which are weak-base prodrugs are activated in an acidic condition and only inhibit H+/K+ATPase that has already been activated. Therefore, the effect of PPIs on acid-related diseases is slow onset and their maximum efficacy can be achieved after several days of dosing, leading to unmet medical needs such as nocturnal acid breakthrough and unsatisfied symptom relief. Methods: We investigated the pharmacological profiles of YH4808, a novel potent, highly selective K+-competitive acid blocker (P-CAB), in terms of hog gastric H+/K+-ATPase activity, gastric acid secretion, and acute gastroesophageal lesions in animal models, in comparison with esomeprazole. In addition, a quantitative whole body autoradiography (QWBA) study was performed with [14C]YH4808 (10 mg/kg) in rats to characterize tissue distribution. Results: YH4808 inhibited H+/K+-ATPase activity in a concentration-dependent manner, with an IC50 value of 3.4 nM which is more potent than that of esomeprazole. The inhibitory mechanism of YH4808 on H+/K+-ATPase was a competitive antagonism to the K+-binding site of H+/K+-ATPase, and it was also a reversible inhibition. In a selectivity assay, YH4808 showed 3,000-fold greater selectivity against Na+/K+-ATPase. In pylorus-ligated rats, oral administration of YH4808 inhibited basal acid secretion in a dose-dependent manner with the ID50 value of 1.1 mg/kg. Anti-secretory activity of YH4808 against histamine-stimulated acid secretion in rats after IV injection (ID50=0.1 mg/kg) was stronger than that of esomeprazole (ID50=0.9 mg/kg). In Heidenhain pouch dogs, IV administration of YH4808 inhibited histamine-stimulated acid secretion in a dose-dependent manner with almost complete inhibition at the dose of 0.6 mg/kg. In a reflux esophagitis model, intraduodenal administration of YH4808 prevented esophageal lesions by 30, 82 and 91% at a dose of 1, 3, and 10 mg/kg, respectively while esomeprazole reduced the lesion by 47% at 10 mg/kg. A QWBA study in rats showed YH4808 accumulated and was retained in the gastric tissue for more than 24h after oral administration. Conclusion: YH4808, a novel selective P-CAB exerted a potent, longer-lasting anti-secretory efficacy through high accumulation in the gastric tissue, which translated into the more effective inhibition of reflux esophagitis than esomeprazole. These findings indicate that YH4808 can provide significant clinical benefits to patients with acid-related diseases.

Discovery, synthesis, and biological evaluation of novel pyrrole derivatives as highly selective potassium-competitive acid blockers

To discover a gastric antisecretory agent more potent than existing proton pump inhibitors, novel pyrrole derivatives were synthesized, and their H+,K+-ATPase inhibitory activities and inhibitory action on histamine-stimulated gastric acid secretion in rats were evaluated. Among the compounds synthesized, compound 17a exhibited selective and potent H+,K+-ATPase inhibitory activity through reversible and K+-competitive ionic binding; furthermore, compound 17c exhibited potent inhibitory action on histamine-stimulated gastric acid secretion in rats and Heidenhain pouch dogs.

Effects of IY-81149, a newly developed proton pump inhibitor, on gastric acid secretion in vitro and in vivo.

The inhibitory effects of IY-81149 (2-[[(4-methoxy-3-methyl)-2- pyridinyl]methyl-sulfinyl]-5-(1H-pyrol-1-yl)-1H-benzimidazole, CAS 172152-36-2), a newly developed proton pump inhibitor (PPI) on gastric acid secretion were investigated in vitro and in vivo. In rabbit parietal cell preparation, IY-81149 irreversibly inhibited H+/K(+)-ATPase in dose-dependent manner with an IC50 of pump inhibitory activity of 6.0 x 10(-6) mol/l and that of omeprazole (CAS 73590-58-6) was 1 x 10(-4) mol/l at pH 7.4. On cumulation of 14C-aminopyrine in histamine stimulated parietal cells, the IC50 of IY-81149 was 9.0 x 10(-9) mol/l and that of omeprazole was 1.9 x 10(-8) mol/l. The inhibition rates of IY-81149 and omeprazole at a concentration of 1 x 10(-9) mol/l in human parietal cells were 137% and 64%, respectively. In pylorus-ligated rats, IY-81149 showed a 2-3 times stronger inhibitory activity than omeprazole against gastric acid secretion. The ED50 of IY-81149 and omeprazole administered intraduodenally was 1.6 mg/kg and 3.8 mg/kg. In the case of oral administration, the ED50 of IY-81149 and omeprazole was 1.94 mg/kg and 5.64 mg/kg, respectively. But after 24 h administration, the anti-secretory activity of IY-81149 was lower than that of omeprazole at all doses tested. In anesthetized rats, IY-81149 dose-dependently increased gastric pH which was lowered by histamine infusion. In the case of i.v. injection, the ED50 of IY-81149 and omeprazole was 1.2 and 1.4 mg/kg and in the case of i.d. administration, the ED50 of IY-81149 and omeprazole was 3.9 and 4.1 mg/kg, respectively. IY-81149 also significantly inhibited pentagastrin-stimulated gastric secretion. Its ED50 was 2.1 mg/kg and that of omeprazole was 3.5 mg/kg with i.d. administration. In the case of i.v. injection, IY-81149 was equipotent to omeprazole. IY-81149 also inhibited gastric acid secretion strongly in fistular rats. The ED50 of IY-81149 administered intraduodenally was 0.43 mg/kg and that of omeprazole was 0.68 mg/kg. In Heidenhain pouch dogs, the acid output was completely blocked at 0.3 mg/kg, 135 min after i.v. administration. Omeprazole showed a similar effect as IY-81149. The histamine induced increase of acid output in the Heidenhain pouch dog was blocked by 71% 150 min after oral administration of enteric-coated IY-81149 at a dose of 3 mg/kg, and omeprazole showed similar effects. In conclusion, IY-81149 revealed the characteristics as a strong proton pump inhibitor, and its potency against gastric acid secretion was superior to that of the reference drug, omeprazole.

N-(2-Hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), a Novel, Potent, and Selective Acid Pump Antagonist for the Treatment of Gastroesophageal Reflux Disease

Inhibition of H(+),K(+)-ATPase is accepted as the most effective way of controlling gastric acid secretion. However, current acid suppressant therapy for gastroesophageal reflux disease, using histamine H(2) receptor antagonists and proton pump inhibitors, does not fully meet the needs of all patients because of their mechanism of action. This study sought to characterize the in vitro and in vivo pharmacology of a novel acid pump antagonist, N-(2-Hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), and to compare it with other acid suppressants. Porcine, canine, and human recombinant gastric H(+),K(+)-ATPase activities were measured by ion-leaky and ion-tight assay. The affinities for a range of receptors, ion channels, and enzymes were determined to analyze selectivity profile. Acid secretion in Ghosh-Schild rats and Heidenhain pouch dogs were measured by titrating perfusate and gastric juice samples. PF-03716556 demonstrated 3-fold greater inhibitory activity than 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine (revaprazan), the only acid pump antagonist that has been available on the market, in ion-tight assay. The compound did not display any species differences, exhibiting highly selective profile including the canine kidney Na(+),K(+)-ATPase. Kinetics experiments revealed that PF-03716556 has a competitive and reversible mode of action. More rapid onset of action than 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-sulfinyl}-benzimidazole (omeprazole) and 3-fold greater potency than revaprazan were observed in Ghosh-Schild rats and Heidenhain pouch dogs. PF-03716556, a novel acid pump antagonist, could improve upon or even replace current pharmacological treatment for gastroesophageal reflux disease.

Pharmacological Profile of Novel Acid Pump Antagonist 7-(4-Fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methyl cyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526)

The pharmacological profiles of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526) were investigated in terms of hog gastric H+,K+-ATPase activity, gastric acid secretion, and acute gastroesophageal lesions in comparison with other proton pump inhibitors (PPIs). CS-526 inhibited H+,K+-ATPase activity in a concentration-dependent manner, with an IC50 value of 61 nM. The inhibitory effect of CS-526 on H+,K+-ATPase activity was more potent than that of any of the other PPIs examined. The inhibitory mechanism of CS-526 on H+,K+-ATPase was a competitive antagonism to the K+ binding site of H+,K+-ATPase, and it was also a reversible inhibition. In pylorus-ligated rats, intraduodenal or oral administration of CS-526 inhibited gastric acid secretion in a dose-dependent manner, and the ID50 values were 2.8 or 0.7 mg/kg, respectively. In Heidenhain pouch dogs, intrapouch administration of CS-526 inhibited histamine-stimulated gastric acid secretion in a dose- and retention time-dependent manner. In a reflux esophagitis model, intraduodenal and oral administration of CS-526 prevented esophageal lesions with ID50 values of 5.4 and 1.9 mg/kg, respectively. Lansoprazole prevented esophagitis only by intraduodenal administration (ID50 = 2.2 mg/kg). Furthermore, CS-526 inhibited acute gastric mucosal lesions. These data demonstrate that the novel acid pump antagonist CS-526 has potent antisecretory and antiulcer effects. These findings indicate that CS-526 would have a curative effect on gastroesophageal reflux disease via its potent antisecretory and antiulcer actions.

Application of a combined effect compartment and binding model for gastric acid inhibition of AR-HO47108: A potassium competitive acid blocker, and its active metabolite AR-HO47116 in the dog

The effect of AR-HO47108, a potassium competitive acid blocker, and its active metabolite AR-HO47116 was studied in Heidenhain pouch dogs following administration of single oral and intravenous doses of the two compounds. The histamine-stimulated acid secretion was measured in different periods after dose up to 24 h. All data obtained in the different studies was pooled and analyzed by non-linear mixed effects modelling. It was found that there is a delay between the plasma concentration–time peak and the maximum inhibitory effect and that the effect persisted longer than anticipated from the plasma concentration half-lives of the compounds. In addition, it was found that the peak effect was reached earlier at higher doses. The effect data was well described by a combined effect compartment and binding model and both distribution to the biophase i.e. the canaliculus of the parietal cell and a rate limiting binding interaction between drug and enzyme appear to contribute to the observed delay. In addition, a secretion rate dependent washout from the biophase may contribute. Furthermore, because the parent compound and metabolite bind to the same enzyme, the effect is determined by competition between the two for the same enzyme. The metabolite was found to be less potent than the parent compound, with K d values of the combined model of 125 and 11.2 nM for the metabolite and parent compound, respectively. However, the metabolite is generated in high concentrations that rapidly exceed the concentration of parent compound after oral administration of parent compound, and this together with its longer plasma half-life will make its contribution to the overall effect increase with time and slightly prolong the duration of the effect.

Duration of the gastric acid antisecretory effect of AZD0865 in dogs

Background/Aim To investigate the duration of antisecretory effect of AZD0865, a potassium-competitive acid blocker (P-CAB), in dogs. Methods Four Heidenhain pouch dogs received single, oral doses of AZD0865 (1 μmol/kg) and a 3.5-h period of histamine stimulation. Acid output was determined 4, 10 or 24h post-dose during stimulation. Secretory responses were also assessed 24h after 5 days' dosing (1 μmol/kg/day). AZD0865 concentration was determined in plasma at each secretory test, and in gastric juice 23–25 h after single dose (reversed-phase liquid chromatography and fluorescence detection). Results Inhibition of acid output (mean±SE), 4, 10 and 24h after single doses, and 24h after 5th dose was 99±1%, 79±2%, 41±5% and 45±3%, respectively. Systemic exposure to AZD0865 was similar after single and repeated doses. Plasma concentrations at 24h were: 4 nmol/L in 1/4 dogs after single dose; <4 nmol/L in 3/4 after single dose and in 4/4 after repeated dose. AZD0865 concentration in gastric juice was 71.9±14.9 nmol/L. Conclusions AZD0865 (1 μmol/kg) provided almost complete blockade of acid secretion 4h after dose, with inhibition lasting >24 h. At 24h, similar levels of inhibition and AZD0865 plasma concentrations occurred after one and several doses. The concentration of AZD0865 in gastric juice was higher than in plasma. This may reflect concentration of AZD0865 in the parietal cell canaliculus. Thus, the duration of effect outlasts the time AZD0865 is detectable in plasma. Clinical Pharmacology & Therapeutics (2005) 77, P15–P15; doi: 10.1016/j.clpt.2004.11.059

Gastric acid secretion in the dog: a mechanism-based pharmacodynamic model for histamine stimulation and irreversible inhibition by omeprazole.

A mechanism-based pharmacodynamic model was used to describe the inhibitory effect by omeprazole on gastric acid secretion measured after histamine stimulation in the dog. The model identifies parameters that are related to the physiological system, the histamine stimulation, and the irreversible effect of omeprazole on the H+, K(+)-ATPase enzyme. Four different experiments with omeprazole (Exps. 1-4) and two placebo experiments were performed in each of the four Heidenhain pouch dogs used. For placebo and experiments 1-3, saline or omeprazole 0.81 mumol/kg was infused during 3 hr with measurements of histamine-stimulated gastric acid secretion in two periods of 3.5-6.5 hr, one period starting just before the omeprazole infusion and a second later period up to 29 hr post infusion. In experiment 4, 0.18 mumol/kg of omeprazole was infused for 22.5 min and gastric juice was collected for 5 hr post infusion. The response data was well described by the model. Similar parameter estimates were obtained by three different analysis methods; naïve pooling, two-stage method and nonlinear mixed effects modeling. The elimination rate constant for the H+, K(+)-ATPase enzyme, kout, was estimated to be 0.040 hr-1, corresponding to a half-life of about 17 hr. This rate constant determines the duration of omeprazole inhibition after long-term exposure. For short-term omeprazole exposure the duration is determined by the rate constant for transfer of enzymes from active to resting state, estimated to be 1.88 hr-1. The second-order rate constant for histamine stimulation was estimated to be 0.064 hr-1 per histamine concentration unit and the maximum acid secretion was estimated to be 5.0 mmol H+/30 min. The second-order rate constant for the irreversible binding of omeprazole to H+, K(+)-ATPase, kome, was estimated to be 2.39 L/mumol.hr. By modeling the histamine-induced baseline response simultaneously with active treatment, predictions of the response are possible not only following different dosing regimens of omeprazole, but also following different degrees of histamine stimulation.

FR145715, a novel histamine H 2 receptor antagonist, with specific anti- Helicobacter pylori activities

The pharmacological profile of N-[3-[2-[ N′-(2-methoxyethyl)guanidino]thiazol-4yl]benzyl-acetamide (FR145715), a novel histamine H 2 receptor antagonist, was examined in both in vitro and in vivo models using experimental animals in comparison with ranitidine. In isolated guinea-pig atria, FR145715 antagonized the effect of histamine on heart rate with approximately three times more potent activity than ranitidine. In in vivo experiments, intraduodenal FR145715 dose-dependently inhibited spontaneous gastric acid secretion in rats (Shay's rats), with a ED 50 value of 18.4 mg/kg, which was comparable to that of ranitidine (30.5 mg/kg). FR145715 also inhibited histamine-stimulated acid secretion in stomach-perfused anaesthetized rats (Schild's rats), when given intravenously and intraduodenally with ED 50 values of 0.59 and 2.72 mg/kg, respectively. Ranitidine displayed more potent activity having respective ED 50 values of 0.10 and 0.17 mg/kg. In Heidenhain pouch dogs, intravenous and oral FR145715 dose-dependently inhibited gastrin-stimulated acid secretion with respective ED 50 values of 0.12 and 0.32 mg/kg, which were similar to those of ranitidine (0.09 and 0.33 mg/kg). In gastric ulcer models, FR145715 dose-dependently inhibited water immersion restraint stress- and acidified aspirin-induced gastric lesions with ED 50 values of 3.2 and 15.1 mg/kg (po), respectively. The comparative compound, ranitidine, also showed beneficial effects on stress-induced gastric ulcers with an ED 50 value of 1.5 mg/kg (po). However, it failed to inhibit acidified aspirin-induced gastric ulcers. FR145715 inhibited HCl-induced gastric lesions in rats, while pre-treatment with indomethacin abolished its beneficial effects, suggesting that FR145715 has a so-called cytoprotective effect which is dependent on endogenous prostaglandin production. In addition to its atypical profile as a histamine H 2 receptor antagonist, FR145715 exhibited strong anti-microbial activities against strains of Helicobacter pylori ( H. pylori) with a mean minimal inhibitory concentration value of 0.32 μg/ml. Moreover, FR145715 showed no anti-microbial effects on 25 other bacteria examined. In addition, in vivo experiments using gnotobiotic piglets infected with H. pylori, FR145715 (16 mg/kg, t.i.d.) completely eliminated the organism with reduced intensity of inflammation, when treated orally for 10 days. These data demonstrate that FR145715 is a novel histamine H 2 receptor antagonist having potent and selective anti- H. pylori activities as well as cytoprotective properties. The present data suggest that FR145715 might be useful for the patients suffering from ulcer relapse, since the drug might be able to eradicate H. pylori in the stomach, which is considered a key factor to cause ulcer recurrence in humans.

The long-lasting effect of TU-199, a novel H+, K(+)-ATPase inhibitor, on gastric acid secretion in dogs.

We have used Heidenhain-pouch dogs to investigate the effects of (+/-)-5-methoxy-2-{[(4-methoxy-3,5-dimethylpyrid-2-yl)methyl]sulph inyl}-1H-imidazo[4,5-b]pyridine (TU-199), an imidazopyridine derivative, on gastric acid secretion stimulated by histamine, carbachol and tetragastrin. We have also investigated the duration of the antisecretory effect of TU-199 using a measurement of intragastric pH for 24 h in gastric fistula dogs whose gastric acid secretion was stimulated by histamine. Single oral administration of TU-199 (0.1, 0.2 and 0.4mgkg(-1)) dose-dependently suppressed gastric acid secretion stimulated by histamine infusion. Oral treatment with TU-199 (0.2, 0.4 and 0.8 mg kg(-1)) also dose-dependently inhibited acid secretion induced by carbachol and tetragastrin. The inhibitory effect of TU-199 on stimulated gastric acid secretion was more potent than that of omeprazole, a well-known H+,K(+)-ATPase inhibitor in dogs. Repeated oral treatment with TU-199 at a dose of 0.2 mg kg(-1) once a day for seven days markedly suppressed histamine-stimulated gastric acid secretion in dogs. This inhibitory effect of TU-199 reached a maximum level after three or four doses and was more pronounced than that of omeprazole or lansoprazole. In gastric fistula dogs, the duration of intragastric pH-elevation by administration of TU-199 (0.3 mg kg(-1)) was much longer than that of omeprazole (0.6mgkg(-1)) or lansoprazole (0.9mgkg(-1)). The IC50 values (doses resulting in 50% inhibition) of TU-199, omeprazole and lansoprazole with regard to H+,K(+)-ATPase activity in dog gastric mucosal microsomes were 8.6, 8.8 and 9.9 microM, respectively. These results indicate that TU-199 inhibits gastric acid secretion via suppression of a H+,K(+)-ATPase activity. Our findings also suggest that TU-199 might have potent and long-lasting effects on gastric acid secretion.

Synthesis and structure-activity relationships of dual histamine H 2 and gastrin receptor antagonists with noncyclic gastrin receptor antagonistic moieties

In order to study structure-activity relationships of dual histamine H 2 and gastrin receptor antagonists as well as to improve their low oral absorbability, their prototype benzodiazepine gastrin receptor antagonistic moieties were altered to a conformationally flexible noncyclic dipeptide equivalent. This skeletal modification significantly potentiated the binding affinity of hybrid compounds for the histamine H 2 receptor, whereas their affinity for the gastrin receptor and receptor selectivity over the CCK-A receptor varied widely with the substituents on the gastrin moiety. Among them, 3-[3-(3-piperidin-1-ylmethylphenoxy)-propylcarbamoyl]propyl carbamic acid 3-[3-((3-methoxyphenyl)[(methylphenylcarbamoyl)methyl]carbamoyl methyl)ureido]benzyl ester ( 7a) showed the highest dual histamine H 2 and gastrin receptor antagonistic activities. It also displayed distinct gastric acid antisecretory activity in vivo for two assays, namely, Schild's rat method by id administration and the rat pylorus ligation method by oral administration. With the latter case, dose-response relationships were observed for the first time, suggesting its substantially improved oral absorbability. However, 7a did not display distinct in vivo gastric acid antisecretory activity for the assay with Heidenhain pouch dogs.

YF476 is a new potent and selective gastrin/cholecystokinin‐B receptor antagonist in vitro and in vivo

We newly synthesized YF476 ((R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2'-pyridyl)-1H-1, 4benzodiazepin-3-yl]-3-(3-methylamino-phenyl)urea) as a gastrin/cholecystokinin-B (CCK-B) receptor antagonist. We investigated the pharmacological profile of YF476 in vitro and in vivo. We examined the binding properties of YF476 to the rat brain, cloned canine and cloned human gastrin/CCK-B receptors, and the effect of YF476 on secretagogue-induced gastric acid secretion in rats and Heidenhain pouch dogs. YF476 replaced the specific binding of [125I]CCK-8 to the rat brain, cloned canine and cloned human gastrin/CCK-B receptors, with Ki values of 0.068, 0.62 and 0.19 nM, respectively. The affinity of YF476 for rat brain gastrin/CCK-B receptor was 4100-fold higher than that for rat pancreatic CCK-A receptor. In anaesthetized rats, intravenous YF476 inhibited pentagastrin-induced acid secretion with an ED50 value of 0.0086 micromol/kg, but did not affect histamine- and bethanechol-induced acid secretion at a dose of 10 micromol/kg. In Heidenhain pouch dogs, intravenous and oral YF476 inhibited pentagastrin-stimulated gastric acid secretion in a dose-dependent manner with ED50 values of 0.018 and 0.020 micromol/kg, respectively, but did not affect histamine-induced acid secretion. These results suggest that YF476 is an extremely potent and highly selective gastrin/CCK-B receptor antagonist, and that the gastrin/CCK-B receptor is not involved in histamine- or bethanechol-induced gastric acid secretion in dogs or rats.

YM022, a potent and selective gastrin/CCK-B receptor antagonist, inhibits peptone meal-induced gastric acid secretion in Heidenhain pouch dogs.

We examined the affinity of YM022, a potent and selective gastrin/CCK-B receptor antagonist, for canine gastrin/CCK-B and CCK-A receptors and the effects of YM022 on secretagogue- and peptone meal-induced acid secretion in the denervated, surgically separated (Heidenhain) canine gastric pouch model in comparison with those of famotidine, an H2-receptor antagonist, and atropine. YM022 inhibited the binding of [(125)I]CCK-8 and [(3)H]devazepide to canine gastrin/CCK-B and CCK-A receptors, with IC50 values of 0.73 and 136 nM, respectively. Intravenous YM022 dose-dependently inhibited pentagastrin- and peptone meal-induced acid secretion with ED50 values of 0.0261 and 0.0654 micromol/kg, respectively, without affecting histamine- or methacholine-induced acid secretion. Famotidine inhibited acid secretion induced by all stimulants, while atropine inhibited the acid secretion induced by every stimulant except histamine. These results indicated that YM022 is a highly potent and selective antagonist for the canine gastrin/CCK-B receptor and suppressed pentagastrin- and peptone meal-induced gastric acid secretion without affecting histamine- or methacholine-induced acid secretion in Heidenhain pouch dogs.

(3R)-N-(1-(tert-butylcarbonylmethyl)-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-(methylamino)phenyl)urea (YF476): a potent and orally active gastrin/CCK-B antagonist.

A number of new 1,4-benzodiazepin-2-one-based gastrin/CCK-B receptor antagonists related to the archetypal analogue L-365,260, and more closely to the recently reported compound YM022, have been synthesized and evaluated for biological activity. The compounds were screened for their ability to inhibit the binding of [125I]CCK-8 to gastrin/CCK-B receptors prepared from rat brains and that of [3H]L-364,718 to CCK-A receptors from rat pancreas, and were shown to be potent and selective ligands for the gastrin/CCK-B receptor. Functional studies in vivo demonstrated the compounds to be antagonists of the receptor as evidenced by their ability to inhibit pentagastrin-induced gastric acid secretion in anesthetized rats. More extensive evaluation in vivo included determination of ED50 values in the rat acid secretion model for selected compounds and an examination of the effect of these compounds on pentagastrin-induced gastric acid secretion in Heidenhain pouch dogs following oral and intravenous administration. Two compounds, i.e. (3R)-N-[1-[(tert-butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5-(2-pyri dyl) -1H-1,4-benzodiazepin-3-yl]-N'-[3-(methylamino)phenyl]urea, 15c (YF476), and (3R)-N-[1-[(tert-Butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5- (2-pyridyl)-1H-1,4-benzodiazepin-3-yl]-N'-[3-(dimethylamino)phenyl ]urea hydrochloride, 15d, showed potent dose-dependent effects in both models with the former showing excellent oral bioavailability and an ED50 of 21nmol/kg po in dogs. 15c is currently under clinical investigation for the treatment of gastro-oesophagal reflux disease (GORD).

O-141 - Local inhibitory effect of leminoprazole on histamine-stimulated gastric acid secretion in Heidenhain pouch dogs

O-141 - Local inhibitory effect of leminoprazole on histamine-stimulated gastric acid secretion in Heidenhain pouch dogs

Pharmacological profiles of a new antiulcer agent, SWR-215.

We investigated the effects of a new antiulcer agent, SWR-215 ([[(1,2-dihydro-2-oxo-4-quinolinyl)methyl]thio]-N-[[[4-(1-piperidinyl methyl)-2-pyridinyl]oxy]-Z-2-butenyl]acetamide), on histamine H2-receptors, gastric acid secretion and various acute experimental gastric lesions. SWR-215 showed unsurmountable histamine H2-antagonism on isolated guinea-pig atrium. In gastric secretion studies, SWR-215 exhibited potent and durable inhibitory effects, and the antisecretory activities were much stronger than that of roxatidine acetate hydrochloride (roxatidine): 5 times stronger on basal acid secretion in pylorus ligated rats, 11 times stronger on histamine-stimulated acid secretion in acute fistula rats, and 2 times stronger on histamine stimulated acid secretion in Heidenhain-pouch dogs, respectively. In various experimental acute gastric lesion studies, SWR-215 potentially inhibited almost all acute gastric and duodenal lesions compared with roxatidine, especially indomethacin-induced and HCl-ethanol-induced gastric lesions, and the inhibitory effects were exhibited at the same or lower doses than those which caused the antisecretory effect. Furthermore, it was considered that the mucosal protective effect of SWR-215 was probably unrelated to the endogenous prostaglandin system in gastric mucosa. These results suggest that SWR-215 possesses both durable antisecretory and mucosal protective effects, and is expected to be a useful drug for the treatment of patients with peptic ulcers.

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 ED 50 values of 2.40 μmol/kg and 4.43 μmol/kg, respectively. In the conscious fistula rat model, doses of 10 μmol/kg IV and 25 μmol/kg PO produced mean peak inhibitions of basal acid output of 91% and 97%, respectively. In these experiments, the duration of action of SK&F 97574 was much shorter than that of the covalent (H +/K +)-ATPase inhibitor, omeprazole. In the conscious Heidenhain pouch dog, SK&F 97574 inhibited histamine-stimulated gastric acid secretion after both intravenous and oral administration with ED 50 values of 0.49 μmol/kg and 0.89 μmol/kg, respectively. In this model, duration of action studies showed that significant residual inhibition of acid secretion remained 8 hours after intravenous dosing with SK&F 97574 (producing peak inhibition of 92%). However, 24 hours after oral dosing of SK&F 97574 (10 μmol/kg), no significant inhibition remained. These data indicate that the duration of action of SK&F 97574 is longer than that of the histamine H 2 receptor antagonists such as cimetidine, but shorter than that of covalent (H +/K +)-inhibitors such as omeprazole. Overall, the pharmacological properties of SK&F 97574 suggest that it could be a potentially useful clinical treatment for acid-related diseases.