Denagliptin (Figure 6) is an advanced compound with a branched side-chain at the P2 position, but also has (4S)-fluoro substitution on the cyanopyrrolidine ring. It is a well-known DPP-4 inhibitor developed by GlaxoSmithKline (GSK). Biological evaluations have shown that the S-configuration of the amino acid portion is essential for the inhibitory activity since the R-configuration showed reluctantly inhibition. These findings will be useful in future designs and synthesis of DPP-4 inhibitors. GSK suspended Phase III clinical trials in October 2008.