Dipeptidyl peptidase IV DPP

The incretin effect is reduced in type 2 diabetes, and this is attributed, at least in part, to reduced secretion of GLP-1. The biological actions of GLP-1 remain essentially intact in type 2 diabetes, but administration of extra GLP-1 is not a practical therapeutic option because the peptide is degraded rapidly if A < 2 min) by the enzyme dipeptidyl peptidase IV (DPP-4). DPP-4 cleaves the N-terminal dipeptide from many of the peptides that have either an alanine or a proline residue penultimate to the N-terminus (Fig. 6). 

Another interesting target for this type of inhibitors is the dipeptidyl peptidase IV (DPP IV). This exodipeptidase, which can cleave peptides behind a proline residue is important in type 2 diabetes as it truncates the glucagon-like peptide 1. Taking into account the P2-Pi( Pro)-P,1 cleavage and the requirement for a free terminal amine, the synthesis of a suicide inhibitor was planned. It looked as if the the e-amino group of a P2 lysine residue could be cyclized because of the relative little importance of the nature of the P2 residue on the rate of enzymatic hydrolysis of known synthetic substrates. Therefore, anew series of cyclopeptides 11 was synthesized (Fig. 11.8). 

Augustyns, K., der Veken, P.V., Senten, K. and Haemers, A. (2005) The therapeutic potential of inhibitors of dipeptidyl peptidase IV (DPP-IV) and related proline-specific dipeptidyl aminopeptidases. Current Medicinal Chemistry, 12, 971-998 (c) Augustyns, K., der Veken, P.V. and Haemers, A. 

A. E. and Kim, D. (2007) Design, synthesis, and biological evaluation of triazolopiperazine-based P-amino amides as potent, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. Bioorganic e[ Medicinal chemistry Letters, 17, 5934-5939. 

Table 2. Percent inhibition of dipeptidyl peptidase IV (DPP IV) by A a j/[ E) C=CF]-Pro derived inhibitors...

K. Zhao, D.S. Lim, T. Funaki, J.T. Welch, Inhibition of dipeptidyl peptidase IV (DPP IV) by 2-(2-amino-1-fluoro-propylidene)-cyclopentanecarbonitrile, a fluoroolefin containing peptidomimetic, Bioorg. Med. Chem. 11 (2003) 207-215. 

The ornithine related phosphonate (n = 3) can be guanidylated at the 4-amino group by treatment with formamidinesulfonic acid to provide Argp(OPh)2. This method can be used for the synthesis of substrate-related thrombin inhibitors such as Ac-Phe-Pro-Argp(OPh)2. 41 Proline analogues required a special approach and a few synthetic methods are reported since dipeptides of Prop(OPh)2 are excellent inhibitors of dipeptidyl peptidase IV (DPP IV or CD 26), the serine protease involved in immune response. 4 Diphenyl phosphite and dialkyl phosphites react smoothly with 1-pyrrolidine (3,4-dihydro-2//-pyrrole) trimer 20 to give the corresponding pyrrolidine-2-phosphonate 21 (Scheme 14). 42 ... 

Several 2-ketoazetidines have shown dipeptidyl peptidase IV (DPP IV) inhibition property <2004BML5579>. 2-Thiazole, 2-benzothiazole and 2-pyridyl ketones were optimal ST binding groups for potency against DPP IV. Both 2-(/ )- and 2-(V)-isomers are equipotent. Certain stabilized azetidin-2-ones maintained their in vitro potency and inhibited DPP IV in the plasma for up to 6h. 

The approval of sitagliptin (1) by the U.S. FDA in 2006 established dipeptidyl peptidase IV (DPP-4) inhibitors as an important new therapy for the treatment of type 2 diabetes.4 7 DPP-4 inhibitors stimulate insulin secretion indirectly by enhancing the action of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (G1P). GLP-1 and G1P stimulate insulin secretion in a... 

Dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5, CD26) is a serine protease cleaving off dipeptides from the amino terminus of peptides or proteins having proline or alanine at the penultimate position. Since prolylamides are known to play a critical role in peptide structure and function, and because of their high resistance toward nonspecific enzymatic hydrolysis, a few enzymes capable of cleaving this structural motif have attracted consid-... 

An X-ray structure of ABT-279 (Figure 20.25), an inhibitor of dipeptidyl peptidase-IV (DPP-IV), bound in the human active site shows an interesting feature Tyr547 and Phe357 of DPP-IV formed a narrow tunnel between their... 

From the viewpoint of anticell invasion/adhesion activity, aminopeptidase-inhibitory activity has been investigated. The structural development studies of thalidomide (48) afforded specific dipeptidyl peptidase IV (DPP-IV) inhibitors [e.g., PPS-33 (55)] and specific puromycin-sensitive aminopeptidase (PSA) inhibitors [e.g., PIQ-22 (56a) PAQ-22 (56b)] (Fig. 8-14) [1-3,7,8,46-48]. DPP-IV appears to be involved in varions pathophysiological effects, inclnding tumor cell adhesion and the entry of hnman immnnodeficiency virus (HIV) into CD4+ T cells, and therefore DPP-IV inhibitors are expected to be... 

Scott R, Herman G, Zhao P, Chen X, Wu M, Stein P. Twelve-week efficacy and tolerability of MK-0431, a dipeptidyl peptidase IV (DPP-IV) inhibitor, in the treatment of type 2 diabetes (T2D) (abstract 41-OR). Diabetes 2005 54(Suppl. 1) A 10-11. 

Al-masri IM, Mohammad MK, Tahaa MO (2009) Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine. J Enzyme Inhib Med Chem 24 1061-1066... 

Nongonierma AB, Fitzgerald RJ (2014) Susceptibility of milk protein-derived peptides to dipeptidyl peptidase IV (DPP-IV) hydrolysis. Food Chem 145 845 852... 

---