As part of an ongoing effort to apply the Deuterated Chemical Entity Platform (DCE Platform�) to clinically validated drugs, several deuterated analogs of the CFTR potentiator ivacaftor (KalydecoTM) have been prepared. The devised synthetic routes allowed for site selective deuterium incorporation with high levels of isotopic purity. Due to the fact that ivacaftor was poorly metabolized in standard liver microsome assays under the conditions tested, human CYP3A4 SupersomesTM were used to assess and compare the in vitro metabolic stability of ivacaftor and the DCEs. In this manner, multiple deuterated analogs displaying marked levels of in vitro metabolic stabilization have been identified. One such analog, compound 110  , exhibited a 55% increase in half-life vs. ivacaftor. Synthetic routes to the individual isotopologs along with metabolic stabilization data using human CYP3A4 SupersomesTM will be presented.

Design and synthesis of deuterated analogs of ivacaftor with enhanced pharmacokinetic properties

246th National Meeting (2013)

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