A novel class of advanced glycation inhibitors ameliorates renal and cardiovascular damage in experimental rat models.
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 (approximately 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.
Izuhara
Yuko
Y
Institute of Medical Sciences and Division of Nephrology, Hypertension and Metabolism, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
Nangaku
Masaomi
M
Takizawa
Shunya
S
Takahashi
Satoru
S
Shao
Jing
J
Oishi
Hisashi
H
Kobayashi
Hiroyuki
H
van Ypersele de Strihou
Charles
C
Miyata
Toshio
T
D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D005663:Furans / Q000627:therapeutic use*; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D007674:Kidney Diseases / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D018384:Oxidative Stress; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
C527492:1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-6-methyl-1,3-dihydrofuro(3,4-c)pyridine-7-ol; D005663:Furans; D017127:Glycation End Products, Advanced; D011725:Pyridines