2. Academic Validation
  3. A pyridone derivative activates SERCA2a by attenuating the inhibitory effect of phospholamban

A pyridone derivative activates SERCA2a by attenuating the inhibitory effect of phospholamban

  • Eur J Pharmacol. 2017 Nov 5;814:1-8. doi: 10.1016/j.ejphar.2017.07.035.
Manami Kaneko 1,  Hisato Yamamoto 2,  Hiroki Sakai 3,  Yusuke Kamada 4,  Toshiki Tanaka 5,  Shuji Fujiwara 6,  Syunsuke Yamamoto 7,  Hiroki Takahagi 8,  Hideyuki Igawa 9,  Shizuo Kasai 10,  Masakuni Noda 11,  Makoto Inui 12,  Tomoyuki Nishimoto 13
Affiliations

Affiliations

  • 1 Cardiovascular and Metabolic Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: manami.kaneko@takeda.com.
  • 2 Department of Pharmacology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan. Electronic address: hisyama@outlook.jp.
  • 3 Department of Pharmacology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan. Electronic address: hirokis@yamaguchi-u.ac.jp.
  • 4 Biomolecular Research Laboratories, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yusuke.kamada1@takeda.com.
  • 5 Cardiovascular and Metabolic Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: toshiki.tanaka@takeda.com.
  • 6 Cardiovascular and Metabolic Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: shuji.fujiwara@takeda.com.
  • 7 Drug Metabolism and Pharmacokinetics Research Laboratories, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: syunsuke.yamamoto@takeda.com.
  • 8 Cardiovascular and Metabolic Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: hiroki.takahagi@takeda.com.
  • 9 Cardiovascular and Metabolic Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: hideyuki.igawa@takeda.com.
  • 10 Cardiovascular and Metabolic Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: shizuo.kasai@takeda.com.
  • 11 Cardiovascular and Metabolic Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: masakuni.noda@takeda.com.
  • 12 Department of Pharmacology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan. Electronic address: minui@yamaguchi-u.ac.jp.
  • 13 Cardiovascular and Metabolic Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: tomoyuki.nishimoto@takeda.com.
PMID: 28734932 DOI: 10.1016/j.ejphar.2017.07.035
Abstract

The cardiac sarco/endoplasmic reticulum CA2+-dependent ATPase 2a (SERCA2a) plays a central role in CA2+ handling within cardiomyocytes and is negatively regulated by phospholamban (PLN), a sarcoplasmic reticulum (SR) membrane protein. The activation of SERCA2a, which has been reported to improve cardiac dysfunction in heart failure, is a potential therapeutic approach for heart failure. Therefore, we developed a novel small molecule, compound A and characterized it both in vitro and in vivo. Compound A activated the CA2+-dependent ATPase activity of cardiac SR vesicles but not that of skeletal muscle SR vesicles that lack PLN. The surface plasmon resonance assay revealed a direct interaction between compound A and PLN, suggesting that the binding of compound A to PLN attenuates its inhibition of SERCA2a, resulting in SERCA2a activation. This was substantiated by inhibition of the compound A-mediated increase in CA2+ levels within the SR of HL-1 cells by thapsigargin, a SERCA inhibitor. Compound A also increased the CA2+ transients and contraction and relaxation of isolated adult rat cardiomyocytes. In isolated perfused rat hearts, the compound A enhanced systolic and diastolic functions. Further, an infusion of compound A (30mg/kg, i.v. bolus followed by 2mg/kg/min, i.v. infusion) significantly enhanced the diastolic function in anesthetized normal rats. These results indicate that compound A is a novel SERCA2a activator, which attenuates PLN inhibition and enhances the systolic and diastolic functions of the heart in vitro and in vivo. Therefore, compound A might be a novel therapeutic lead for heart failure.

Keywords

Ca(2+) handling; Inotropic effect; Lusitropic effect; Phospholamban; Sarco/endoplasmic reticulum Ca(2+)-dependent ATPase 2a.

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