Ischemic heart disease (IHD) is associated with an increase in reactive oxygen species (ROS), which can modify Nav1.5 and result in an enhanced late Na+ current (Late INa, INaL). In IHD enhanced INaL leads to calcium overload, which in turn activates CAMKII and further increases INaL, creating a vicious cycle. Within its therapeutic range, (2 � 8 �M) ranolazine (Ran, 1  ) selectively inhibits late INa compared to peak INa, but also inhibits other cardiac ionic currents, including IKr. Herein, we report the discovery of a potent and selective Late INa inhibitor, triazolopyridine GS-458967 (2  ), which has suitable PK profile consistent with QD dosing. Enhanced late INa generated by Anemonia sulcata toxin II (ATX-II) was inhibited by Ran (1  ) and GS-458967 (2  ) with IC50's of 6.9 and 0.25 �M, respectively. GS-458967 (2  ) was >50 times more potent than Ran (1  ) in reducing ischemia-induced contracture in an isolated heart model (rat) of global no-flow ischemia. GS-458967 represents a new class of potent late INa inhibitors that will be useful in further delineating the role of inhibitors of this current in the treatment of IHD.

Discovery of a cardiac late sodium current inhibitor (Na<sub>v</sub> 1.5) GS-458967, a triazolopyridine, structurally distinct from ranolazine with improved intrinsic efficacy and potency

247th National Meeting (2014)

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Discovery of a cardiac late sodium current inhibitor (Nav 1.5) GS-458967, a triazolopyridine, structurally distinct from ranolazine with improved intrinsic efficacy and potency

Discovery of a cardiac late sodium current inhibitor (Na_v 1.5) GS-458967, a triazolopyridine, structurally distinct from ranolazine with improved intrinsic efficacy and potency