A series of novel N-acylsulfonamide prodrugs were evaluated and profiled as inhibitors of MEK kinase.  Our pursuit of MEK inhibitors led us to compound 1  , which displayed highly potent and selective inhibition of MEK enzymatic and cellular activities.  However, compound 1 had poor solubility and no oral exposure in rats.  Using a prodrug approach, solubility and pharmacokinetic parameters of a series of MEK inhibitors were improved, culminating in the discovery of the propionyl sulphonamide 7  .  Optimization led to the discovery of compound 7  , which showed improved solubility and PK.  This poster describes the SAR leading to compound 7 and the multi-species in vitro and in vivo PK to support compound 7  as a potential candidate.

Evaluation of N-acyl sulfonamide prodrug inhibitors of MEK kinase

243rd National Meeting (2012)

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