Acetyl CoA Carboxylase (ACC) is a key lipid handling enzyme involved in the processes of both fatty acid oxidation (FAO) and de novo lipogenesis (DNL). ACC inhibition therefore offers a potentially novel approach to the treatment of metabolic diseases and type 2 diabetes. In our search for novel inhibitors of ACC, we identified molecules with significant in vitro activity, but were plagued by poor absorption when delivered orally, making assessment of pharmacodynamic outcomes unreliable. The team then applied a prodrug strategy to improve plasma exposure of parent drug. We hereby detail the synthesis and pharmacokinetic evaluation of a number of prodrugs, all of which improved plasma exposure of the corresponding parent alcohol. Species differences between the prodrugs will also be discussed.

Improving exposure of ACC inhibitors via a prodrug strategy

245th National Meeting (2013)

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