Small-molecule inhibitor: saxagliptin

Name

History
Peptidases inhibited: Inhibits dipeptidyl-peptidase IV.
Mechanism: Saxagliptin forms a covalent but reversible bond between S630 of dipeptidyl-peptidase IV and the inhibitor nitrile carbon, and the catalytic residues contribute to formation of the complex (Metzler et al., 2008).

CID at PubChem: 44590597
ChEBI: 618213
Structure
Chemical/biochemical name: (1R,3R,5R)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile
Formula weight: 315
Related inhibitors: Saxagliptin belongs to 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.

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).