Ssu-Hui Wu

A three-dimensional pharmacophore model for dipeptidyl peptidase IV inhibitors

Dipeptidyl peptidase IV (DPP-IV) is a valid drug target for type-2 diabetes and DPP-IV inhibitors have been proven to efficiently improve glucose tolerance. In our study, 3D pharmacophore models were generated using a training set of 22 DPP-IV inhibitors. The best model consisted of important chemical features and mapped well into the active site of DPP-IV. The model gave high correlation coefficients of 0.97 and 0.84 for the training set and the test set, respectively, showing its good predictive ability for biological activity. Furthermore, the pharmacophore model demonstrated the capability to retrieve inhibitors from database with a high enrichment factor of 42.58. All results suggest that the model provides a useful tool for designing novel DPP-IV inhibitors.

Rational design and synthesis of potent and long-lasting glutamic acid-based dipeptidyl peptidase IV inhibitors

A series of (2S)-cyanopyrrolidines with glutamic acid derivatives at the P2 site have been prepared and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV). The structure-activity relationships (SAR) led to the discovery of potent 3-substituted glutamic acid analogues, providing enhanced chemical stability and excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. Compound 13f exhibited the ability to both significantly decrease the glucose excursion and inhibit plasma DPP-IV activity.

Novel trans-2-aryl-cyclopropylamine analogues as potent and selective dipeptidyl peptidase IV inhibitors

A series of trans-2-aryl-cyclopropylamine derived compounds were synthesized and evaluated their biological activities against DPP-IV. The structure-activity relationships (SAR) led to the discovery of novel series of DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. The studies identified a potent and selective DPP-IV inhibitor 24b, which exhibited the ability to both significantly inhibit plasma DPP-IV activity in rats and improve glucose tolerance in lean mice and diet induced obese mice.

Analogues of 2-phenyl-ethenesulfonic acid phenyl ester have dual functions of inhibiting expression of inducible nitric oxide synthase and activating peroxisome proliferator-activated receptor γ

We identified a series of 2-phenyl-ethenesulfonic acid phenyl ester analogues as novel dual-function agents that suppressed nitric oxide production in lipopolysaccharide/interferon gamma-stimulated RAW264.7 cells and activated peroxisome proliferator-activated receptor gamma (PPARgamma) in a cell-based transactivation assay. Western blot analysis demonstrated that these compounds inhibit the expression of inducible nitric oxide synthase protein, and scintillation proximity assay validated their ability to bind to PPARgamma. Our studies provide the basis for developing these dual-function agents for anti-inflammation and anti-atherosclerosis therapy.