Synthesis and preliminary characterization of a novel antiarrhythmic compound (KB130015) with an improved toxicity profile compared with amiodarone.
Recent developments in antiarrhythmic therapy have indicated that the best approach to pharmacologically controlling supraventricular arrhythmias and life-threatening ventricular tachyarrhythmias is by prolonging cardiac repolarization rather than by blocking conduction. In this context, amiodarone has emerged as the most potent compound, but its universal use has been limited by its toxicity profile. There are data to suggest that an important component of amiodarones antiarrhythmic action might be mediated via inhibition of thyroid hormone action in the heart. Therefore, a new series of carboxymethoxybenzoyl and benzyl derivatives of benzofuran has been prepared and evaluated as thyroid hormone receptor antagonists. Within this series, 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran KB130015 (7) was found to reveal the most promising in vitro data. It inhibits the binding of (125)I-T(3) to the human thyroid hormone receptors (hThR) alpha(1) and beta(1). T(3)-Antagonism was confirmed in reporter cell assays employing CHOK1 cells (Chinese hamster ovary cells) stably transfected with hThR alpha(1) or hThR beta(1) and an alkaline phosphatase reporter gene downstream a thyroid response element. The derived IC(50) values were 2.2 microM for hThR alpha(1) and 4.1 microM for hThR beta(1). Compound 7 was selected for further characterization of chronic effects on ventricular papillary muscle by transmembrane electrophysiology after daily intraperitoneal injection of the ligand (40 mg/kg body weight) in guinea pigs. Compound 7 was found to prolong the action potential duration at 90% (APD(90)) repolarization time (219 +/- 22 ms, control: 186 +/- 9 ms, p < 0.01) without exhibiting any reverse rate dependency of action in a manner similar to that of amiodarone. In general, preliminary tolerance experiments with 7 demonstrated an improved safety profile compared to that of amiodarone. In summary, 7 appears to be less toxic than amiodarone while maintaining its electrophysiologic properties consistent with antiarrhythmic activity. Its potential antiarrhythmic actions warrant further investigations.
Carlsson
Bo
B
Karo Bio AB, Novum, Huddinge S-141 57, Sweden.
Singh
B N
BN
Temciuc
Marcel
M
Nilsson
Stefan
S
Li
Yi-Lin
YL
Mellin
Charlotta
C
Malm
Johan
J
D000200:Action Potentials; D000638:Amiodarone / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D020746:Calcium Channels, L-Type / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D006224:Cricetinae; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008111:Liver Function Tests; D011869:Radioligand Assay; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors / Q000235:genetics; D013960:Thyroid Function Tests; D014162:Transfection
D000889:Anti-Arrhythmia Agents; D001572:Benzofurans; D020746:Calcium Channels, L-Type; C446946:KB 130015; D011988:Receptors, Thyroid Hormone; D002784:Cholesterol; D000638:Amiodarone