Unique binding mode of Evogliptin with human dipeptidyl peptidase IV.

Evogliptin ((R)-4-((R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl) piperazine-2-one)) is a highly potent selective inhibitor of dipeptidyl peptidase IV (DPP4) that was approved for the treatment of type 2 diabetes in South Korea. In this study, we report the crystal structures of Evogliptin, DA-12166, and DA-12228 (S,R diastereomer of Evogliptin) complexed to human DPP4. Analysis of both the structures and inhibitory activities suggests that the binding of the trifluorophenyl moiety in the S pocket and the piperazine-2-one moiety have hydrophobic interactions with Phe357 in the S extensive subsite, and that the multiple hydrogen bonds made by the (R)-β-amine group in the S pocket and the contacts made by the (R)-tert-butyl group with Arg125 contribute to the high potency observed for Evogliptin.

Dipeptidyl peptidase-4 inhibitor with β-amino amide scaffold: synthesis, SAR and biological evaluation.

Inhibitors of dipeptidyl peptidase-4 (DPP4) have been shown to be effective treatments for type 2 diabetes. Several series of β-amino amide containing piperazine derivatives have been prepared and evaluated as a inhibitor of DPP4. Finally compound 5m was selected for further evaluation.

DA-1229, a novel and potent DPP4 inhibitor, improves insulin resistance and delays the onset of diabetes.

Aim: To characterize the pharmacodynamic profile of DA-1229, a novel dipeptidyl peptidase (DPP) 4 inhibitor.

Main Methods: Enzyme inhibition assays against DPP4, DPP8 and DPP9. Antidiabetic effects of DA-1229 in HF-DIO mice and young db/db mice.

Purification and characterization of a cytosolic Ca(2+)-independent phospholipase A(2) from bovine brain.

The Ca(2+)-independent phospholipase A(2) (iPLA(2)) subfamily of enzymes is associated with arachidonic acid (AA) release and the subsequent increase in fatty acid turnover. This phenomenon occurs not only during apoptosis but also during inflammation and lymphocyte proliferation. In this study, we purified and characterized a novel type of iPLA(2) from bovine brain.

Discovery of DA-1229: a potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.

A series of β-amino amide containing substituted piperazine-2-one derivatives was synthesized and evaluated as inhibitors of dipeptidyl pepdidase-4 (DPP-4) for the treatment of type 2 diabetes. As results of intensive SAR study of the series, (R)-4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butanoyl]-3-(t-butoxymethyl)-piperazin-2-one (DA-1229) displayed potent DPP-4 inhibition pattern in several animal models, was selected for clinical development.

Synthesis and biological evaluation of chromone carboxamides as calpain inhibitors.

Excessive calpain activations contribute to serious cellular damage and have been found in many pathological conditions. Novel chromone carboxamides derived from ketoamides were prepared and evaluated for mu-calpain inhibition. Among synthesized, compound 2i was the most potent calpain inhibitor with an IC(50) value of 0.