Noboru Kaneko, Christopher M. Loughrey, Godfrey Smith, Ryuko Matsuda, Tomoko Hasunuma, Patric B. Mark, Masashi Toda, Makoto Shinozaki, Naoyuki Otani, Scott Kayley, Ana Da Silva Costa, Tamara P. Martin, Sara Dobi, Priyanka Saxena, Ken Shimamoto, Tetsuya Ishikawa, Ryuichi Kambayashi, Alexandra Riddell, Elspeth B. Elliott, Charlotte S. McCarroll, Toshiya Sakai, Yamano Mitsuhisa, Sayuri Hirano, Takeshi Kitai, Kengo Kusano, Yuko Inoue, Masahiko Nakamura, Migaku Kikuchi, Shigeru Toyoda, Isao Taguchi, Toshihiko Fujiwara, Atsushi Sugiyama, Yuji Kumagai, Kunio Iwata
{"title":"新型雷诺丁受体 2 抑制剂 M201-A 可增强利尿作用、肾功能和延缓衰老作用：临床前和 I 期研究","authors":"Noboru Kaneko, Christopher M. Loughrey, Godfrey Smith, Ryuko Matsuda, Tomoko Hasunuma, Patric B. Mark, Masashi Toda, Makoto Shinozaki, Naoyuki Otani, Scott Kayley, Ana Da Silva Costa, Tamara P. Martin, Sara Dobi, Priyanka Saxena, Ken Shimamoto, Tetsuya Ishikawa, Ryuichi Kambayashi, Alexandra Riddell, Elspeth B. Elliott, Charlotte S. McCarroll, Toshiya Sakai, Yamano Mitsuhisa, Sayuri Hirano, Takeshi Kitai, Kengo Kusano, Yuko Inoue, Masahiko Nakamura, Migaku Kikuchi, Shigeru Toyoda, Isao Taguchi, Toshihiko Fujiwara, Atsushi Sugiyama, Yuji Kumagai, Kunio Iwata","doi":"10.1111/bph.16379","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background and Purpose</h3>\n \n <p>The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca<sup>2+</sup> homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies.</p>\n </section>\n \n <section>\n \n <h3> Experimental Approach</h3>\n \n <p>Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca<sup>2+</sup> leak via RyR2 and intracellular Ca<sup>2+</sup> concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg<sup>−1</sup> once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses.</p>\n </section>\n \n <section>\n \n <h3> Key Results</h3>\n \n <p>In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca<sup>2+</sup> leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability.</p>\n </section>\n \n <section>\n \n <h3> Conclusions and Implications</h3>\n \n <p>The novel drug M201-A inhibited diastolic Ca<sup>2+</sup> leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.</p>\n </section>\n </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.16379","citationCount":"0","resultStr":"{\"title\":\"A novel ryanodine receptor 2 inhibitor, M201-A, enhances natriuresis, renal function and lusi-inotropic actions: Preclinical and phase I study\",\"authors\":\"Noboru Kaneko, Christopher M. Loughrey, Godfrey Smith, Ryuko Matsuda, Tomoko Hasunuma, Patric B. Mark, Masashi Toda, Makoto Shinozaki, Naoyuki Otani, Scott Kayley, Ana Da Silva Costa, Tamara P. Martin, Sara Dobi, Priyanka Saxena, Ken Shimamoto, Tetsuya Ishikawa, Ryuichi Kambayashi, Alexandra Riddell, Elspeth B. Elliott, Charlotte S. McCarroll, Toshiya Sakai, Yamano Mitsuhisa, Sayuri Hirano, Takeshi Kitai, Kengo Kusano, Yuko Inoue, Masahiko Nakamura, Migaku Kikuchi, Shigeru Toyoda, Isao Taguchi, Toshihiko Fujiwara, Atsushi Sugiyama, Yuji Kumagai, Kunio Iwata\",\"doi\":\"10.1111/bph.16379\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background and Purpose</h3>\\n \\n <p>The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca<sup>2+</sup> homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Experimental Approach</h3>\\n \\n <p>Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca<sup>2+</sup> leak via RyR2 and intracellular Ca<sup>2+</sup> concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg<sup>−1</sup> once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Key Results</h3>\\n \\n <p>In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca<sup>2+</sup> leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions and Implications</h3>\\n \\n <p>The novel drug M201-A inhibited diastolic Ca<sup>2+</sup> leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. 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A novel ryanodine receptor 2 inhibitor, M201-A, enhances natriuresis, renal function and lusi-inotropic actions: Preclinical and phase I study
Background and Purpose
The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies.
Experimental Approach
Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg−1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses.
Key Results
In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability.
Conclusions and Implications
The novel drug M201-A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.
期刊介绍：
The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries.
Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues.
In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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