Progress toward the Development of a Safe and Effective Agent for Treating Reentrant Cardiac Arrhythmias:  Synthesis and Evaluation of Ibutilide Analogues with Enhanced Metabolic Stability and Diminished Proarrhythmic Potential

Abstract

A series of ibutilide analogues with fluorine substituents on the heptyl side chain was prepared and evaluated for class III antiarrhythmic activity, metabolic stability, and proarrhythmic potential. It was found that fluorine substituents stabilized the side chain to metabolic oxidation. Many of the compounds also retained the ability to increase the refractoriness of cardiac tissue at both slow and fast pacing rates. The potential for producing polymorphic ventricular tachycardia in the rabbit model was dependent on the chirality of the benzylic carbon. The S-enantiomers generally had less proarrhythmic activity than the corresponding racemates. One compound from this series (45E, trecetilide fumarate) had excellent antiarrhythmic activity and metabolic stability and was devoid of proarrhythmic activity in the rabbit model. It was chosen for further development.

Synthesis and Evaluation of Fluorinated Fingolimod (FTY720) Analogues for Sphingosine-1-Phosphate Receptor Molecular Imaging by Positron Emission Tomography

“…Fluorination of diol 2 with DAST in DCM gave the known 18 33 in low yield. 34 Scheme 2 presents the synthesis of the 4-hydroxy analogue and the ω-fluorinated 4-hydroxy analogue of 2. Compounds 19 and 20 were synthesized by reduction of 10 and 12 using sodium borohydride and lithium chloride in THF/EtOH.…”

Recent Advances in Drug Therapy for Atrial Fibrillation

“…One of the compounds under evaluation for treatment of AF is trecetilide, an analogue of ibutilide. This I Kr blocker seems to have excellent antiarrhythmic properties and did not exert proarrhythmic activity despite significant prolongation of ventricular refractoriness 107 . The bradycardic agent tedisamil differs from most other Class III agents by blocking I to in addition to I Kr .…”

Synthesis of (E)- and (Z)-α,β-difluorourocanic acid

“…If the directive effect of fluorine (resulting in stabilization of an α-carbonium ion) is strong enough to take precedence over aryl carbonium ion stabilization, "FBr" addition would be predicted to lead to the geminal instead the desired vicinal difluoro compounds. Indeed, this is the observed product of addition of FBr to vinyl fluorides where an aryl group is not present [8] or when the aryl group and fluorine are on the same carbon [9]. To our surprise, we have found no examples of electrophilic additions to 1-alkyl-2-aryl-1-fluoroalkenes.…”