Ion channel modulators

Recent drug development studies have centered on the capacity of known antiepileptic drugs (AEDs) to interact with ion channels, and it is now established that several agents appear to be exerting their effects primarily by inhibiting ion channels. Modulation of neuronal sodium channels decreases cellular excitability and the propagation of nerve impulses. Inhibition of sodium channels appears to be a major component of the mechanism of action of several anticonvulsant drugs. 

V. K. Gribkoff, J. E. Starrett, Jr. (2002). Advances in technologies for the discovery and characterization of ion channel modulators Focus on potassium channels. Annu. Rep. Med. Chem. 37 237. 

Ion channel modulation represents another approach to positive inotropy [13]. Sodium channel modulators increase Na+ influx and prolong the plateau phase of the action potential sodium/calcium exchange then leads to an increase in the level of calcium available to the contractile elements, thus increasing the force of cardiac contraction [13,14]. Synthetic compounds such as DPI 201-106 and BDF 9148 (Figure 1) increase the mean open time of the sodium channel by inhibiting channel inactivation [15]. Importantly, BDF 9148 remains an effective positive inotropic compound even in severely failing human myocardium [16] and in rat models of cardiovascular disease [17]. Modulators of calcium and potassium channel activities also function as positive inotropes [13], but in the remainder of this article we shall focus on sodium channel modulators. 

Sit, S.-Y. and Meanwell, N. A., (Bristol-Myers Squibb) 4-Aryl-3-hydroxyquinolin-2-one derivatives as ion channel modulators, W09823273. 

Hunter, J.C. Voltage-gated ion channel modulators in Novel aspects of pain management. Opioids and beyond, edited by J. Sawynok and A. Cowan. Wiley-Liss. Inc., 1999, 321-344. 

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Fraser SP, Grimes JA, Djamgoz MB (2000) Effects of voltage-gated ion channel modulators on rat prostatic cancer cell proliferation comparison of strongly and weakly metastatic cell lines. Prostate 44 61-76... 

Suessbrich H, Busch AE, Scherz MW (1997) The pharmacology of cloned cardiac potassium channels. Ion Channel Modulators 2 432-439... 

Morpholino derivatives, (IV) and (V), prepared by Beatch, (4,5), respectively, were effective as ion channel modulating agents and used in the treatment of arrhythmia. 

Application of this topological framework analysis to ion channel modulators yields access to privileged ion channel chemotypes. Conversion of these frameworks into appropriate scaffolds for synthesis allows subsequent building of ion channel focused libraries. 

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