Article ID Journal Published Year Pages File Type
1370848 Bioorganic & Medicinal Chemistry Letters 2011 5 Pages PDF
Abstract

The identification of a potent, selective, and orally available MK2 inhibitor series is described. The initial absence of oral bioavailability was successfully tackled by moving the basic nitrogen of the spiro-4-piperidyl moiety towards the electron-deficient pyrrolepyridinedione core, thereby reducing the pKa and improving Caco-2 permeability. The resulting racemic spiro-3-piperidyl analogues were separated by chiral preparative HPLC, and the activity towards MK2 inhibition was shown to reside mostly in the first eluting stereoisomer. This led to the identification of new MK2 inhibitors, such as (S)-23, with low nanomolar biochemical inhibition (EC50 7.4 nM) and submicromolar cellular target engagement activity (EC50 0.5 μM).

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Physical Sciences and Engineering Chemistry Organic Chemistry
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