Saxagliptin

spinqualitylabelsall models Saxagliptin, better known as Onglyza, (3bjm) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D 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 Cmax and AUC and a potentially improved side effect profile. Increasing evidence that all DPP-4 inhibitors can to certain malignant cancers. 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. 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. 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.

Pharmacokinetics

DPP4 Inhibitor Hyperglycemia & Type II Diabetes Parameter Diabetes (Galvus) Sitagliptin (Januvia) Saxagliptin (Onglyza) Vildagliptin (hr) 1.75 1-4 2 Cmax (ng/ml) 290 330 34 AUC (%) 85 87 67 Pharmaceutical Drugs (%) 9 38 0 glucose metabolism (hr) 2-3 12.4 2.5 Diabetes (ng/ml/hr) 1610 3470 101 insulin (nM) 3 18 50 Renal Clearance (L/h) 13.0 21.0 13.8 Volume Distribution (L) 71 198 151 Dosage (mg) 100 100 5 Metabolism Hydrolysis Hepatic (CYP3A4 & CYP2C8) Hepatic (CYP3A4) For Pharmacokinetic Data References, see: References

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