DPPIV inhibitors

In a series of reports on their class of DPPIV inhibitors [27-29], workers from Merck have shown that the incorporation of an acid moiety (or related bioisostere) into an amine-containing template to furnish a zwitterionic system has been ofuse in minimizing hERG activity. For example, incorporation of an acid bioisostere into the biaryl P-methylphenylalanine template has been shown to afford enhancements in selectivity over hERG (cf. compounds 40 and 41) [29]. A concomitant reduction in oral bioavailability was observed between the two compounds, which underlines the main limitation in this approach. 

In the synthesis of amino boronic acid dipeptides 7 (Scheme 11.37) as inhibitors of the serine protease dipeptidyl peptidase IV (DPPIV), Kelly and co-workers have reported an elegant preparation of the optically active proline boronic acid (boroPro) by a direct lithiation of N-Boc-pyrrolidine and a quench with B(OMe)3. The subsequent hydrolysis and resolution with (-1-)-pinanediol provided rapid access to a key chiral intermediate in the synthesis of these dipeptides. The direct a-functionalisation approach avoided a catal5Aic hydrogenation step required in their original synthesis starting from IV-Boc-pyrrole. ... 

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