ABSTRACT-Effectsof KB-5492, a new anti-ulcer agent, on various experimental gastric mucosal lesions and mucosal defensive factors in rats were compared with those of teprenone and cimetidine. KB-5492 administered orally at 12.5 200 mg/kg inhibited water-immersion stress and indomethacin-induced gastric mucosal lesions in a dose-dependent manner with ED50 values of 46 and 27 mg/kg, respectively, indicat ing that KB-5492 was more potent than teprenone but less potent than cimetidine. KB-5492, administered orally at 12.5 -100 mg/kg, also inhibited ethanol-induced gas tric mucosal lesions in a dose-dependent manner with an ED50 of 23 mg/kg, so KB 5492 was 3 times more potent than teprenone, whereas cimetidine produced no ob vious inhibition. In addition, KB-5492, administered orally at 25 and 50 mg/kg twice daily for 10 consecutive days, significantly accelerated the healing of acetic acid-in duced gastric ulcers more potently than teprenone and cimetidine. KB-5492 at anti ulcer doses significantly increased gastric mucosal blood flow in normal anesthetized rats and inhibited the reduction of gastric mucosal hexosamine content induced by aspirin, but did not affect gastric acid secretion in pylorus-ligated rats. These results indicate that KB-5492 has potent and broad anti-ulcer properties, which are probably exerted by its enhancement of gastric mucosal defensive factors through increasing gastric mucosal blood flow and/or retaining gastric mucus, and not by its inhibition of gastric acid secretion.It is generally accepted that peptic ulcers are caused by a disruption in the balance of aggressive factors (gastric acid and pepsin) and mucosal defensive factors (blood flow, mucus, HC03 secretion, etc.) (1). Anti-ulcer agents have therefore been used either for suppres sing aggressive factors or for enhancing mucosal defensive factors. However, in recent years, it has been considered that different anti-ulcer agents should be used for gastric and duodenal ulcers, because of the patho physiological differences between the two ulcer types. That is, as gastric acid secretion is generally greater in duodenal ulcer patients than in normal subjects (2-4), agents such as H2-receptor antagonists or proton pump in hibitors, which strongly inhibit gastric acid secretion, show prominent effects on duodenal ulcers. In contrast, since gastric acid secretion is usually normal or below normal in gastric ulcer patients, gastric ulcers are presumed to be caused by weaknesses in gastric mucosal re sistance (4, 5). Therefore, agents which en hance mucosal defensive factors would be ex pected to show desirable effects against gastric ulcers. Although various agents in this catego ry have already been developed so far, they have not been particularly effective, so anti secretory agents are used preferably, even in the treatment of gastric ulcers.Seeking a novel agent which would enhance mucosal defensive factors more potently than existing agents, we developed 4-methoxy phenyl 4-(3,4,5-trimethoxybenzyl)-1-piperazine acetate monofumarate m...

Abstract-Effects of a newly synthesized compound, KB-5492, on gastric lesions and gastric secretion were studied in rats.

ABSTRACT-The effect of KB-5492, a new anti-ulcer agent with a selective affinity for the sigma-receptor, on aspirin-induced disruption of the gastric mucosal barrier was studied in rats. Intragastric instillation of aspirin at 200 mg/kg rapidly decreased the gastric transmucosal potential difference (PD) in anesthetized rats. The PD recovered gradually following the removal of aspirin from the instillation solution. Aspirin, ad ministered orally at 200 mg/kg, also reduced the amount of gastric covering mucus and induced a decrease in gastric H+ concentration and an increase in gastric Na+ concentration in pylorus-ligated rats. KB-5492, administered intraduodenally at 200 mg/kg, significantly prevented the aspirin-induced decrease in PD and accelerated the recovery of PD. In addition, KB-5492 at 200 mg/kg significantly prevented the reduction of gastric covering mucus, the decrease in gastric H+ concentration and the increase in gastric Na+ concentra tion induced by aspirin. These effects were similar to those of 0.01 mg/kg of 16,16-dimethyl prostaglandin E2 (dmPGE2). Teprenone at 200 mg/kg did not show any effect except for the inhibitory effects on the changes in gastric H+ and Na+ concentration. In the histological study, marked reduction of PAS-positive epithelial mucus and the exfoliation of surface epithelial cells were observed in the gastric mucosa exposed to aspirin. KB-5492 and dmPGE2 almost completely prevented the former, whereas both drugs prevented the latter incompletely. These findings indicate that KB-5492 protects the gastric mucosal barrier against the disruption by aspirin, which may be mainly exerted by retention of the gastric covering mucus.

No abstract

No abstract

A series of ester derivatives of1-benzy1-4-piperazineacetic acid was synthesized and evaluated as antiulcer agents.Quantitative structure-activity relationships(QSAR)analyses by using the ALS (adaptive least-squares)method were performed in each step to decrease the synthetic efforts.The QSAR for the esters is much the same as that for the previously examined amide derivatives.The antiulcer activity of these compounds was considered to be based on the cytoprotective activity.The most active and the least toxic compounds,5nand5y,were selected for further study.Keywords-benzylpiperazine derivative;1-piperazineacetate;quantitative structure-activity relationship;ALS method;antiulcer activityIn the past few years there has been increasing interest in gastrointestinal mucosal defensive factors against damaging agents,and in compounds which stimulate the defensive mechanisms.In the course of our study to search for antiulcer agents with cytoprotective activity,we found that some derivatives of 1-benzy1-4-piperazineacetamides(1)meet the requirements.2)Quantitative structure-activity relationship(QSAR)study of these derivatives revealed that1-(2,3,4-or3,4,5-trimethoxybenzyl)-4-piperazineacetamides with small NRR' groups are preferable.1)If the smallness itself is the condition of potent antiulcer activity,then the NRR'groups are replaceable with other small groups.With this thought in mind,we prepared some ester analogs of1and examined their antiulcer activity.This paper deals with not only syntheses and antiulcer activity of the esters(5)but also QSAR analyses of these derivatives by using the adaptive least-squares(ALS)3)method.

The piperazine (I) is coupled with the alkyl iodides (II), the acyl chlorides (IV), and the aromatic aldehydes (VI) to give the derivatives (III), (V), and (VII).

From a search for antiulcer agents with cytoprotective activity by random screening, 1-(pyrrolidinocarbonylmethyl)-4-(2,3,4-trimethoxybenzyl)piperazine dimaleate (4h) was found as a lead compound.Analogues of 4h were synthesized and evaluated for antiulcer activity as well as toxicity. Four compounds (4h, p, w, x) exhibited potent antiulcer activity in several gastric ulcer models and low toxicity without any antisecretory activity. The antiulcer activity of these compounds was considered to be based on the cytoprotective activity.Keywords-benzylpiperazine; 1-piperazineacetamide; random screening; antiulcer activity; cytoprotective activity; antisecretory activityIt has been stated that peptic ulcers are induced by an imbalance between the aggressive factors such as acid or pepsin and the gastrointestinal mucosal resistance to the aggressive factors,2) and that acid secretion is critical to the duodenal ulcer, while gastric ulcer is mainly induced by weakening of the defensive factors.3) Thus, antiulcer agents are generally classified into two categories, antisecretory agents which suppress the aggressive factors and cytoprotective agents which strengthen the defensive mechanisms of the gastrointestinal mucosa. However, for the purpose of the treatment and prophylaxis of peptic ulcers, it is desirable to use an antiulcer agent with an excellent cytoprotective activity.4) StrategyThere are various antiulcer agents which have cytoprotective activity, including cetraxate hydrochloride, sucralfate and teprenone. The structures of the known agents are quite diverse, as shown in Chart 1, but not all of these agents have sufficient activity, so that it does not seem likely to be fruitful to study derivatives of these agents in order to develop an antiulcer agent having more potent cytoprotective activity. Therefore, in order to find such an agent, random screening was considered to be appropriate.Experimental acute gastric ulcers are generally classified into four types; pylorus ligationinduced ulcer, drug-induced ulcer, stress-induced ulcer and necrotizing agent-induced ulcer . Among these models, pylorus ligation-induced ulcer was mainly used to identify antisecretory agents; other models are considered useful to find antiulcer agents with cytoprotective activity.5) Thus, a facile indomethacin-induced ulcer model (a drug-induced ulcer model) was selected as a first screening method. A compound which showed a statistically significantly different result from the control at a dose of 200 mg/kg was judged to be active, and the oral toxicity (LD50) was examined in mice. For active compounds with low toxicity, antisecretory activity and antiulcer activity against other ulcer models were examined and compared to those of known cytoprotective agents.