1,4:3,6-Dianhydrohexitol nitrate derivatives. II. Synthesis and antianginal activity of aryl- or arylcarbonylpiperazine derivatives.
A series of 5-(4-aryl- or 4-arylcarbonylpiperazin-1-yl)-5-deoxy-1,4: 3,6-dianhydro-L-iditol 2-nitrates was prepared in order to obtain orally active, nitrate-type vasodilators with reduced side effects. Our drug design was based on a small reduction in the lipophilicity compared to that of 5-deoxy-5-[4-(3-phenylthiopropyl)piperazin-1-yl]-1,4: 3,6-dianhydro-L-iditol 2-nitrate (1, KF14124). Compounds 4h (aryl = benzimidazol-2-yl), 4i (arylcarbonyl = nicotinoyl), and 4w (arylcarbonyl = 3-furoyl) showed potent anti-ischemic activity in a lysine-vasopressin-induced angina pectoris model (rats), and their structure-activity relationships are discussed. Compound 4i exhibited potent vasodilation of the coronary artery in anesthetized dogs and also exhibited potent preload reduction in a heart failure model (dogs) as compared with isosorbide dinitrate (2), nicorandil (3), and KF14124 (1). Furthermore, 4i showed much weaker acute lethal toxicity and less central nervous system depression than 1 in mice. Thus, 4i (KW-3196) is under development as a vasodilator and a drug for treating angina pectoris.
Hayashi
H
H
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Ikeda
J
J
Kubo
K
K
Moriyama
T
T
Karasawa
A
A
Suzuki
F
F
D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D015195:Drug Design; D005260:Female; D006333:Heart Failure / Q000188:drug therapy; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008236:Lypressin; D008297:Male; D051379:Mice; D017202:Myocardial Ischemia / Q000188:drug therapy*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
D010879:Piperazines; D014665:Vasodilator Agents; C083109:KF 14124; D008236:Lypressin; D007548:Isosorbide Dinitrate