DPP-IV Inhibition

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. 

Based on the analysis of the DPP-IV ciystal stmctures [90-%] and the interpretation of the stracmre-activity relationship data, both the lipophiUc S, pocket and the Glu205/Glu206 (fyad can be considered as cmcial molecular anchors for DPP-IV inhibition [78], Moreover, this conclusion is supported by results derived from two different energetic pharmacophores [97,98] obtained by our group that have quantified the relative contribution of the different pharmacophore sites to the intermo-lecular interactions with DPP-IV. The first energetic pharmacophore was built from the PDB stracture of ten complexes of DPP-IV with potent (ICj values < 10 nM) reversible inhibitors of a nonpeptide nature (Fig. 7.3a) [99]. This study showed that... 

We next used a slightly modified version of the VS woikflow to evaluate an in-house database of 29,779 natural products annotated with their natural source. We were able to identily 84 molecules (isolated from 95 different natural sources) that were predicted to inhibit DPP-fV [ 120]. An exhaustive bibliographic search revealed that we predicted 12 potential DPP-fV inhibitors from 12 different plant extracts that are known to have antidiabetic activity (Table 7.5). Six of these 12 molecules are identical or similar to molecules with described antidiabetic activity (although their role as DPP-IV inhibitors has not been suggested as an explanation for their bioactivity Table 7.5). Therefore, it is plausible that these 12 molecules could be partially responsible for the antidiabetic activity of these extracts through DPP-IV inhibition [120]. In addition, we identified six potential DPP-IV inhibitor molecules from six... 

Bharti SK, Krishnan S, Kumar A, Rajak KK, Murari K, Bharti BK, Gupta AK (2012) An-tihypeiglycemic activity with DPP-IV inhibition of alkaloids from seed extract of Cas-tanospermum austrak investigation by experimental validation and molecular docking. Phytomedicine 20 24-31... 

Molecules 11 rapidly and irreversibly inhibit the DPP IV activity of the CD26 antigen, with IC50 values in the nanomolar range. Cycle enlargement ( = 4 instead of 2) improves inhibitory activity, whereas increasing the alkyl chain length on the sulfur atom R has no apparent effect. Other aminopeptidases are not inhibited. Molecules 11 inhibit DPP I V-p, an isoform of DPP IV, much more poorly.32,56... 

The preparation of the fluoroolefin amide isosteres is reviewed. The incorporation of the amide isosteres in peptidomimetics and the influence of that isosteric substitution on biological activity on inhibition of peptidyl prolyl isomerases cyclophilin (CyP) and Pini, dipeptidyl peptidase IV/CD26 (DPP IV) and thermolysin is described. In addition, select fiuoroolefination procedures which may have utility in the construction of fluoroolefin amide isosteres are illustrated. 

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

Interestingly, the selectivity of the hydoxamic acid inhibitor of DPP IV was crucial in experiments to establish the role and existence of quiescent cell proline dipeptidase, QPP, a serine protease whose inhibition leads to the death of quiescent peripheral blood monocytes [104]. All other DPP IV inhibitors did not exhibit sufficient selectivity to discriminate between DPP IV and QPP. 

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. 

There are other closely related DPP enzymes, such as DPP 8 and DPP 9. When these enzymes are inhibited in experimental animals multiorgan toxicity occurs. Sitaghptin appears to be highly selective for DPP IV and has 2600 times selectivity for DPP IV compared with DPP 8 and DPP9. Compared with placebo, sitaghptin produces an approximately two-fold increase in postprandial active glucagon-like peptide 1 concentrations (2). 

Sitaglipin (oral) increases HDLc, causes weight loss. Inhibits DPP-IV thereby potentiating the HbAlc reductions of Recently approved. 

Recent studies indicated that in addition to the regnlation of postprandial gly-cemia, DPP-IV may have pleiotropic effects (e.g., obesity, tumor growth, and HIV infection), which makes it an attractive target for drug discovery research [27-32]. DPP-IV inhibitors block the degradation of GLP-1 and inhibit the inactivation of several other peptides that may have vasoactive and cardioprotective effects... 

A number of DPP-IV inhibitors have recently been tested for selectivity to DPP-IV, FAP, DPP8, and DPP9 enzymes [45]. In that study, individually selective compounds for DPP-IV, DPP8/9, and FAP were identified, which allowed an evaluation of the potential toxicity and tolerability of each type of inhibition The DPP8/9... 

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