A novel anti-ischemic ATP-sensitive potassium channel (K(ATP)) opener without vasorelaxation: N-(6-aminobenzopyranyl)-N'-benzyl-N' '-cyanoguanidine analogue.
This paper describes the design, synthesis, and biological evaluation of a novel anti-ischemic compound, (2S,3S,4R)-N-(6-amino-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-benzopyranyl)-N'-benzyl-N"-cyanoguanidine (33), and the structure-activity relationships leading to the discovery of this compound. Compound 33 significantly reduced the myocardial infarct zone to area at risk (IZ/AAR) in the ischemic myocardium rat model with high cardioselectivity. Since the cardioprotective effect of compound 33 is reversed by ATP-sensitive potassium channel (K(ATP)) blockers, its anti-ischemic effect appears to be at least mediated by K(ATP) opening. In addition, compound 33 shows good protective activity on neuronal cells against oxidative stress, and therefore it is suggested that compound 33 may have therapeutic potential both in cardio- and in neuroprotection.
Yoo
S E
SE
Bioorganic Division and Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology, Taejon 305-600, Korea. seyoo@krict.re.kr
Yi
K Y
KY
Lee
S
S
Suh
J
J
Kim
N
N
Lee
B H
BH
Seo
H W
HW
Kim
S O
SO
Lee
D H
DH
Lim
H
H
Shin
H S
HS
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015640:Ion Channel Gating; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D015221:Potassium Channels / Q000819:agonists* / Q000378:metabolism; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects*
D002316:Cardiotonic Agents; D006146:Guanidines; C438686:N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine; D018696:Neuroprotective Agents; D015221:Potassium Channels; D011714:Pyrans; D000255:Adenosine Triphosphate