Development research on rebamipide (Mucosta) began 28 years ago. Back in 1979. At that time, H2 Procker, represented by Tagamet, was the most popular drug for treating gastric ulcers. However, based on its corporate philosophy of pursuing originality, Otsuka Pharmaceutical embarked on the development of a completely new type of therapeutic drug other than H2 Procker. The company's instructions were, ``An anti-ulcer drug different from H2 Procker.'' The research was accompanied by many difficulties. The research was conducted at Otsuka Pharmaceutical Co., Ltd.'s Tokushima Research Institute.
Otsuka Pharmaceutical's drug discovery has major characteristics. It is a quinolinone skeleton. There are many drugs that have this basic structure, including Michelan, Meptin, Pletal, and Abilify. Mucosta research began based on the accumulated data. From the beginning of development, it was decided that this compound with a quinolinone skeleton would be the starting point. At the time, there was a group at the institute studying the relationship between beta-stimulants and gastric acid secretion, but Mucosta's work was a small project. It may not have been a highly anticipated project. It was known that various effects can be exerted by changing the position of the side chain of the quinolinone skeleton, and a substituent at the 4-position was assigned to mucosta. We screened compounds surrounding quinolinone for their inhibitory effects on gastric acid secretion using pylorus-ligated rats and gastric reflux rats. As a secondary screening, we investigated the anti-ulcer effect in various experimental ulcer models.
In the so-called acute ulcer models, such as the aspirin ulcer and indomethacin ulcer models, compounds that suppress gastric acid secretion showed mostly good results, but in the chronic ulcer model, which was the final evaluation system for drug efficacy, it was difficult to heal. The researchers found themselves at a loss each day, as they either failed to advance the project or delayed it. Just before receiving the news from the company that their research was suddenly suspended, the researchers gathered and spent the night talking about what was needed to overcome this current situation. Discussions such as whether it is okay to suppress important gastric acid or the fact that ulcers have already developed in the patient's gastrointestinal tract have come up that completely negate the evaluation process that we have used up until now. In the end, everyone agreed on a completely opposite screening procedure, using the chronic ulcer model in which the drug's efficacy had previously been confirmed for primary screening. At that time, primary screening was started using the acetic acid ulcer model, which was said to be unsuitable as a screening model. I think it is not hard to imagine why it is not suitable for screening, but it takes nearly two weeks to make a judgment, and it requires a large number of samples and a large amount of compounds, and the various requirements of the primary screening model. This is because all of the requirements were not met. However, the organic synthesis team patiently continued to synthesize the large amount of compounds needed. I still believe that no research institute, including overseas, has adopted this method. Although we started screening using an acetic acid ulcer model, we were unable to find any compounds that promoted healing. In the meantime, they discovered a group of compounds that promoted healing, albeit weakly, in a group of structures similar to Mucosta, and by intensively screening the surrounding area, five compounds containing Mucosta were eventually discovered. Ta. Mucosta was confirmed to inhibit the development of gastric ulcers not only in chronic ulcer models, but also in acute ulcer models, such as stress ulcers, although long-term oral administration is required. However, the problem was that the mechanism of action of Mucosta to promote healing was not understood. Measuring gastric acid secretion did not affect gastric juice secretion, nor did it show any changes in digestive enzymes such as pepsin. However, a large amount of mucus-like material was observed in the gastric fluid of rats collected by ligating the pylorus. While we researchers were perplexed, we casually read the journal of the American College of Gastroenterology and the word site protection jumped out at us. A paper by A. obet et al. showed that prostaglandins in the gastric mucosa control the defense mechanism that protects the stomach wall from gastric acid and pepsin, thereby maintaining mucosal homeostasis. Furthermore, if prostaglandin is administered, the gastric mucosa will remain normal even if necrosis-inducing substances are subsequently administered into the stomach. Moreover, a number of papers were published showing that similar effects can be obtained by increasing prostaglandin endogenously. We discovered a major clue here and investigated prostaglandin concentrations in the gastric mucosa of a group of compounds that promoted healing in chronic ulcers. The healing-promoting effect and the prostaglandin-increasing effect were then clearly correlated, and Mucosta, which had the highest activity, was selected as the final candidate. In the process of conducting basic experiments, new findings were discovered one after another that determined Mucosta's superiority. These findings led to the following questions: ``Why does Mucosta suppress the gastric ulcer model induced by nonsteroidal anti-inflammatory drugs that deplete prostaglandins?'' and ``Why does Mucosta suppress recurrence in the rat acetic acid ulcer recurrence model?'' It is based on two major experimental facts.
From the beginning of its development to the present, many researchers have conducted vigorous research on Mucosta, and new medicinal effects have been discovered. In particular, research related to gastric inflammation has shown that 1) suppression of inflammatory cell infiltration in the gastric mucosa, 2) ability to scavenge active oxygen, 3) suppression of inflammatory cytokines, 4) suppression of activated leukocyte adhesion molecules, 5 )H. It has been reported that pyloi has an inhibitory effect on gastric mucosal cell adhesion. Mucosta's inhibitory effect on reactive oxygen species was first reported using chemiluminescence methods using lucigenin and luminol. Subsequently, using electron spin resonance, it was revealed that Mucosta was approximately 2.5 times more reactive to dimethyl sulfoxide (DMSO), a typical scavenger for the most damaging hydroxyl radical. Structural deletion sites were also identified. Mucosta can be said to be a very powerful eraser. Furthermore, it has been revealed one after another that it suppresses superoxide production from activated neutrophils.
In the treatment of peptic ulcers, H. The development of pyloi eradication therapy has provided a clear answer to the problem of recurrence of peptic ulcers, especially duodenal ulcers, which had not been resolved by conventional drug treatments. However, the goals of peptic ulcer treatment are said to be to improve subjective symptoms, promote healing, prevent complications, and prevent recurrence. I think it must be said that there are still issues that need to be resolved, including those after pyloi eradication. Furthermore, non-H. pyloi peptic ulcer exists, the pathological condition varies from patient to patient, and the treatment policy changes depending on the healing phase. It will be prescribed. From a therapeutic perspective, Mucosta introduced in this report is a drug that has been researched and developed with a focus on the phenomenon of inflammation within the gastric mucosa, and in the future there will be important questions such as why it is effective. It is believed to be one of the few drugs that can answer questions. Currently, Mucosta is sold in nine countries around the world, including Japan, China, and South Korea. As mentioned above, development in the United States was abandoned due to the Western belief that suppression of gastric acid secretion is the most important thing to prevent ulcers. It may be said that it is a drug that has been applied.