Molecular hybridization, synthesis, and biological evaluation of novel chroman I(Kr) and I(Ks) dual blockers.
The combination of I(Kr) and I(Ks) blockade could lead to synergistic and safe class III anti-arrhythmic effect with the enhanced efficacy and reduced risk. On the rationale of structural hybridization of azimilide and HMR-1556, a novel series of I(Kr) and I(Ks) dual blockers were designed, synthesized and evaluated in vitro. One compound, 3r (CPUY11018), deserves further evaluation for its potent anti-arrhythmic activity and favorable cardiovascular profile.
Du
Lupei
L
Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Jiangsu 210009, China.
Li
Minyong
M
Yang
Qian
Q
Tang
Yiqun
Y
You
Qidong
Q
Xia
Lin
L
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002839:Chromans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009693:Nucleic Acid Hybridization; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002839:Chromans; C420023:HMR 1556; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; C059983:potassium channel protein I(sk)