Small-molecule inhibitor: NVP-DPP728

Name

History: NVP-DPP728 was described by Hughes et al. (1999) as an inhibitor of dipeptidyl-peptidase IV.
Peptidases inhibited: Inhibits dipeptidyl-peptidase IV.
Mechanism: Dipeptidyl-peptidase IV is reversibly inhibited with K_i 11 nM (Hughes et al., 1999). This compound is of the nitrile class of serine peptidase inhibitors. Inhibition of thrombin by a tripeptide nitrile was described by Stuber et al. (1988), but nitriles were generally considered poor inhibitors of serine peptidases (as contrasted with cysteine peptidases) until potent inhibition of dipeptidyl-peptidase IV (DPP IV) and prolyl oligopeptidase by aminoacylpyrrolidine-2-nitrile derivatives was reported (Li et al., 1995; Li et al., 1996). 2-Cyanopyrrolidine compounds came to form an important class of DPP IV inhibitors.
Pharmaceutical relevance: By inhibition of dipeptidyl-peptidase IV, and thus slowing the degradation of glucagon-like peptide 1, NVP-DPP728 reduces glycemia, and has the potential for use in the treatment of type 2 diabetes (Ahren et al., 2002).

Structure
Chemical/biochemical name: 1-[[[2-[(5->cyanopyridin-2-yl) amino]ethyl] amino] acetyl]-2-cyano-(S)-pyrrolidine

Inhibitor class: This compound is one of the "gliptins" that are inhibitors of dipeptidyl-peptidase IV, and have been developed for potential use as drugs in the treatment of type 2 diabetes. These compounds suppress the degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide by dipeptidyl-peptidase IV. This helps to correct the defective insulin and glucagon secretion characteristic of this form of diabetes by stimulating insulin secretion and suppressing glucagon release (Chahal & Chowdhury, 2007; Thornberry & Gallwitz, 2009).