A novel class of advanced glycation inhibitors ameliorates renal and cardiovascular damage in experimental rat models

Yuko Izuhara, Masaomi Nangaku, Shunya Takizawa, Satoru Takahashi, Jing Shao, Hisashi Oishi, Hiroyuki Kobayashi, Charles Van Ypersele De Strihou, Toshio Miyata

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background. The reno- and cardiovascular-protective effects of angiotensin II receptor blockers (ARBs), have been ascribed, at least in part, to their ability to inhibit the formation of advanced glycation end products (AGEs), independently of their effect on blood pressure. They act through decreased oxidative stress, unlike previously reported AGE inhibitors which entrap reactive carbonyl (RCOs) precursors of AGEs. The hypotensive effects of ARBs', however, may limit their use. In the present study, we report the synthesis of a new AGE inhibitor, TM2002, and its effects in vitro and in vivo. Methods. We screened a large chemical library (∼1300 compounds) including edaravone, a drug used to treat cerebral infarction, for in vitro AGE inhibitory activity. Based upon the structure-function analysis of edaravone derivatives, we synthesized a novel AGE inhibitor, 1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4- yl)-6-methyl-1,3-dihydro-furo[3,4-c]pyridine-7-ol (TM2002). We delineate in vitro the biological characteristics of TM22002, evaluate in vivo its toxico-pharmacokinetics and document in animal models of rat, their renal and cardiovascular protective effectiveness. Results. Screening of a large chemical library disclosed that edaravone inhibits in vitro AGE formation efficiently. Unfortunately, like most AGE inhibitors, it also traps pyridoxal, limiting its clinical usefulness. We therefore synthesized a novel AGE inhibitor, TM2002, that does not trap pyridoxal. In vitro, TM2002 shows powerful AGE inhibitory activity. Markers of oxidation, i.e. o-tyrosine formation and transition metal chelation, are efficiently inhibited by TM2002-like ARBs. TM2002 does not bind to the angiotensin II type 1 receptor. It is readily bioavailable and non-toxic. In vivo, TM2002, given acutely or for 8 weeks, has no adverse effects. In four different rat models of renal injury (anti-Thy1 and ischaemia-reperfusion) and cardiovascular injury (carotid artery balloon injury and angiotensin II-induced cardiac fibrosis), TM2002 improves renal and cardiovascular lesions without modification of blood pressure. Conclusions. TM2002 is a novel, non-toxic AGE inhibitor acting through ARB-like mechanisms, able to prevent renal and cardiovascular diseases independently of blood pressure lowering.

Original languageEnglish
Pages (from-to)497-509
Number of pages13
JournalNephrology Dialysis Transplantation
Volume23
Issue number2
DOIs
Publication statusPublished - 2008 Feb 1
Externally publishedYes

Keywords

  • Advanced glycation end products
  • Blood pressure
  • Oxidative stress
  • Radical scavenge
  • Renoprotection

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

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    Izuhara, Y., Nangaku, M., Takizawa, S., Takahashi, S., Shao, J., Oishi, H., Kobayashi, H., Van Ypersele De Strihou, C., & Miyata, T. (2008). A novel class of advanced glycation inhibitors ameliorates renal and cardiovascular damage in experimental rat models. Nephrology Dialysis Transplantation, 23(2), 497-509. https://doi.org/10.1093/ndt/gfm601