Mibefradil (Posicor�) was a T-type calcium-channel blocker withdrawn from the market in 1998 due to serious drug-drug interactions.  The potent MBI of CYP3A4 by mibefradil resulted in a marked increase in exposure for the co-administered drugs and the resulting adverse events.  There is no mechanistic understanding of the inhibition of CYP3A4 by mibefradil; however, recent data point to a reactive species that results in heme destruction.  As part of our site-specific deuteration platform, we prepared deuterated analogs of mibefradil and performed in vitro studies of their metabolic properties.   These results are presented.

Design and synthesis of mibefradil analogs to study the mechanism based inactiviation of CYP3A4

244th National Meeting (2012)

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