text: In general, DPP-4 inhibitors are not very stable compounds. Therefore, many researchers focus on enhancing the stability for cyanopyrrolidines. The most widespread technique to improve chemical stability is to incorporate a steric bulk. The two cyanopyrrolidines that have been most pronounced, vildagliptin and saxagliptin, were created in this manner. K579 is a DPP-4 inhibitor discovered by researchers at Kyowa Hakko Kyogo. It had improved not only chemical stability but also a longer-lasting action. That long-lasting action was most likely due to slow dissociation of the enzyme-inhibitor complex and an active oxide metabolite that undergoes enterohepatic circulation. The discovery of the active oxide was in fact a big breakthrough as it led to the development of vildagliptin and saxagliptin. One major problem in DPP-4 inhibitor stability is intramolecular cyclization. The precondition for the intramolecular cyclization is the conversion of the trans-rotamer, which is the DPP-4 binding rotamer (Figure 5). Thus, preventing this conversion will increase stability. This prevention was successful when incorporating an amide group into a ring, creating a compound that kept the DPP-4 inhibitory activity that, did not undergo the intramolecular cyclization and was even more selective over different DPP enzymes. It has also been reported that a cyanoazetidine in the P1 position and a β-amino acid in the P2 position increased stability.