Developing drugs of a new class for the treatment against obesity and metabolic syndromes: synthesis of chemical compounds that inhibit ARIA

• Project/Area Number: 26670406
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Kobe Pharmaceutical University
• Principal Investigator: IKEDA KOJI 神戸薬科大学, 薬学部, 准教授 (90423871)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肥満 / メタボリック症候群 / 脂肪血管新生 / ARIA / 脂肪組織 / 血管新生 / PTEN

Outline of Final Research Achievements

ARIA-KO mice were resistant against obesity and obesity-related metabolic syndromes. We previously identified a compound (C30) that inhibits ARIA function. Here we analyzed effects of compounds structurally related to C30 on ARIA functions. We picked up 70 compounds and analyzed their inhibitory effect on ARIA. Four C30-like compounds practically inhibited ARIA function, and they all contain the same basic structure. However, these four compounds showed less inhibitory effect on ARIA function comparing to C30, while they showed lower cytotoxicity than C30.
We then tried to establish a new assay method for compound screening for ARIA-inhibitor, and constructed cell free alpha-screening system that could detect inhibitory effect of compounds against ARIA.

Research Products

• [Journal Article] Diabetes-related ankyrin repeat protein (DARP/Ankrd23) modifies glucose homeostasis by modulating AMPK activity in skeletal muscle (2015)
  • Author(s): Shimoda Y, Matsuo K, Kitamura Y, Ono K, Ueyama T, Matoba S, Yamada H, Wu T, Chen J, Emoto N, Ikeda K
  • Journal Title: PLos ONE Volume: 10(9) Issue: 9 Pages: e0138624-e0138624
  • DOI: 10.1371/journal.pone.0138624
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension. (2015)
  • Author(s): Satwiko MG, Ikeda K, Nakayama K, Yagi K, Hocher B, Hirata K, Emoto N.
  • Journal Title: Biochem Biophys Res Commun. Volume: 465 Issue: 3 Pages: 356-362
  • DOI: 10.1016/j.bbrc.2015.08.002
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Loss of Apoptosis regulator through modulating IAP expression (ARIA) protects blood vessels from atherosclerosis (2015)
  • Author(s): Matsuo K, Akakabe Y, Kitamura Y, Shimoda Y, Ono K, Ueyama T, Matoba S, Yamada H, Hatakeyama K, Asada Y, Emoto N, Ikeda K
  • Journal Title: J Biol Chem Volume: 290(6) Issue: 6 Pages: 3784-3792
  • DOI: 10.1074/jbc.m114.605287
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Signaling crosstalk between endothelial cell and mature adipocyte regulates adipose tissue angiogenesis and homeostasis (2015)
  • Author(s): Koji Ikeda
  • Organizer: 日本分子生物学会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2015-12-04
  • Invited
• [Presentation] A novel angiogenic adipokine Neuregulin-4 preserves metabolic homeostasiss by regulating adipose tissue angiogenesis (2015)
  • Author(s): Dhite Bayu Nugroho, Koji Ikeda, Agian Jeffilano Barinda, Donytra Arby Wardhana, Ken-ichi Hirata, Noriaki Emoto
  • Organizer: American Heart Association Scientific Session
  • Place of Presentation: Orlando, FL
  • Year and Date: 2015-11-08
  • Int'l Joint Research