Saxagliptin

Better Known as: Onglyza

• Marketed By: Bristol-Myers Squibb & AstraZeneca
• Major Indication: Hyperglycemia & Type II Diabetes
• Drug Class: Dipeptidyl Peptidase-4 (DPP-4) Inhibitor
• Date of FDA Approval (Patent Expiration): 2009 (2021)
• Projected Sales Peak: $1 Billion
• Importance: It is the most recent drug treating Diabetes to be approved by the FDA. Effectiveness at nearly 20-fold lower doses compared to Sitagliptin & Vildagliptin, allowing for dramatically reduced C_max and AUC and a potentially improved side effect profile. Increasing evidence that all DPP-4 inhibitors can to certain malignant cancers.^[1]
• See Pharmaceutical Drugs for more information about other drugs and diseases.

Mechanism of Action

Dipeptidyl Peptidase-4 (DPP-4) is a membrane serine exopeptidase that cleaves proline dipeptides form the N-terminal end of protein substrates. DPP-4 plays a major role in glucose metabolism as it is responsible for the degradation of incretins, most notably Glucagon-like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP). Incretins are a group of gastrointestinal hormones that stimulate insulin biosynthesis and inhibit glucagon secretion after consuming high glucose meals. Since Diabetes is typically caused by a deficiency in insulin secretion or by increased hepatic glucose production, preventing incretin degradation is a viable treatment approach for diabetics. Saxagliptin is a competitive inhibitor of DPP-4. By inhibiting DPP-4 and subsequently preventing the enzymatic degradation of GLP-1 and GIP, these incretins are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas, resulting in controlled blood-glucose levels.^[2] Saxagliptin binds to the active site pocket of DPP-4 within a tunnel capable of binding incretin compounds and situating their N-terminus in the active site.^[3] This active site contains several crucial residues for binding including: Glu 206, Glu 205, Asp 663, Tyr 662, Asn 710, Val 711, His 740, Trp 629, Ser 630, Try 631, Tyr 547, Tyr 666, & Phe 357. Saxagliptin forms 7 hydrogen bonds with DPP-4 and a rare, reversible covalent bond with Ser 630, which appears to be formed with the help of His 740.^[4]