<P> 2 . Presence of a nitrile moiety on the pyrrolidine ring is critical to achieving potent activity </P> <P> Also, systematic SAR investigation has shown that the ring size and stereochemistry for the P2 position is quite conditioned . A 5 - membered ring and L - configuration has shown better results than a 4 - membered or 6 - membered ring with D - configuration . Only minor changes on the pyrrolidine ring can be tolerated, since the good fit of the ring with the hydrophobic S1 pocket is very important for high affinity . Some trials have been made, e.g. by replacing the pyrrolidine with a thiazoline . That led to improved potency but also loss of chemical stability . Efforts to improve chemical stability often led to loss of specificity because of interactions with DPP - 8 and DPP - 9 . These interactions have been connected with increased toxicity and mortality in animals . There are strict limitations in the P1 position and hardly any changes are tolerated . On the other hand, a variety of changes can be made in the P2 position . In fact, substitution with quite big branched side chains, e.g. tert - butylglycin, normally increased activity and chemical stability, which could lead to longer - lasting inhibition of the DPP - 4 enzyme . It has also been noted that biaryl - based side chains can also give highly active inhibitors . It was originally believed that only lipophilic substitution would be tolerated . Now it is stated that also the substitution of polar negatively charged side - chains as well as hydrophilic substitution can lead to excellent inhibitory activity . </P> <P> 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 . </P> <P> Vildagliptin (Galvus) (Figure 6) was first synthesized in May 1998 and was named after Edwin B. Villhauer . It was discovered when researchers at Novartis examined adamantyl derivatives that had proven to be very potent . The adamantyl group worked as a steric bulk and slowed intramolecular cyclization while increasing chemical stability . Furthermore, the primary metabolites were highly active . To avoid additional chiral center a hydroxylation at the adamantyl ring was carried out (Figure 6). The product, vildagliptin, was even more stable, undergoing intramolecular cyclization 30 - times slower, and having high DPP - 4 inhibitory activity and longer - lasting pharmacodynamic effect . </P>

Who invented a polypeptide for replacing bond material in the body