Indolylmaleimide Derivative IM-17 Shows Cardioprotective Effects in Ischemia-Reperfusion Injury

Kosuke Dodo; Tadashi Shimizu; Jun Sasamori; Kazuyuki Aihara; Naoki Terayama; Shuhei Nakao; Katsuya Iuchi; Masahiro Takahashi; Mikiko Sodeoka

doi:10.1021/acsmedchemlett.7b00454

Indolylmaleimide Derivative IM-17 Shows Cardioprotective Effects in Ischemia-Reperfusion Injury

ACS Med Chem Lett. 2018 Jan 29;9(3):182-187. doi: 10.1021/acsmedchemlett.7b00454. eCollection 2018 Mar 8.

Authors

Kosuke Dodo^{1

2

3

4}, Tadashi Shimizu^{1

3}, Jun Sasamori⁵, Kazuyuki Aihara⁵, Naoki Terayama^{1

4}, Shuhei Nakao^{1

4}, Katsuya Iuchi^{1

2}, Masahiro Takahashi³, Mikiko Sodeoka^{1

2

4}

Affiliations

¹ RIKEN, Synthetic Organic Chemistry Laboratory, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan.
² Sodeoka Live Cell Chemistry Project, ERATO, JST, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan.
³ Institute of Multidisciplinary Research for Advanced Materials (IMRAM), Tohoku University, 2-1-1, Katahira, Aoba, Sendai, Miyagi 980-8577, Japan.
⁴ AMED-CREST, AMED, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
⁵ Drug Research Department, Fukushima Research Laboratories, Toa Eiyo Ltd., 1,Yuno-tanaka, Iizaka-machi, Fukushima-shi, Fukushima 960-0280, Japan.

Abstract

We previously developed IM-54 as a novel type of inhibitor of hydrogen-peroxide-induced necrotic cell death. Here, we examined its cell death inhibition profile. IM-54 was found to selectively inhibit oxidative stress-induced necrosis, but it did not inhibit apoptosis induced by various anticancer drugs or Fas ligand, or necroptosis. IM-17, an IM derivative having improved water-solubility and metabolic stability, was developed and confirmed to retain necrosis-inhibitory activity. IM-17 showed cardioprotective effects in an isolated rat heart model and an in vivo arrhythmia model, suggesting that IM derivatives may have therapeutic potential.