A Novel Anti-Ischemic ATP-Sensitive Potassium Channel (K ATP) Opener without Vasorelaxation:  N-(6-Aminobenzopyranyl)-N‘-benzyl-N‘ ‘-cyanoguanidine Analogue

• Published in: Journal of medicinal chemistry 2001-11, Vol.44 (24), p.4207-4215
• Main Authors: Yoo, Sung-eun, Yi, Kyu Yang, Lee, Sunkyung, Suh, Jeehee, Kim, Nakjeong, Lee, Byung Ho, Seo, Ho Won, Kim, Sun-Ok, Lee, Dong-Ha, Lim, Hong, Shin, Hwa Sup
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Aorta - drug effects; Aorta - physiology; Biological and medical sciences; Cardiotonic Agents - chemical synthesis; Cardiotonic Agents - chemistry; Cardiotonic Agents - pharmacology; Cardiovascular system; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - metabolism; Guanidines - chemical synthesis; Guanidines - chemistry; Guanidines - pharmacology; Ion Channel Gating; Male; Medical sciences; Miscellaneous; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Myocardial Infarction - pathology; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Oxidative Stress - drug effects; Pharmacology. Drug treatments; Potassium Channels - agonists; Potassium Channels - metabolism; Pyrans - chemical synthesis; Pyrans - chemistry; Pyrans - pharmacology; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship; Vasodilation - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010183f

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.