Sitagliptin

spinqualitylabelsall models Sitagliptin, better known as Januvia, (1x70) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Better Known as: Januvia Marketed By: Merck & Co. Major Indication: Hyperglycemia & Type II Diabetes Drug Class: Dipeptidyl Peptidase-4 (DPP-4) Inhibitor Date of FDA Approval (Patent Expiration): 2006 (2017) 2009 Sales: $2.4 Billion Importance: One of the best selling treatments for Type II Diabetes. Often used in combination with Metformin, the first line anti-diabetic medication (Combination sold as Janumet). Has an excellent side-effect profile with a relatively low incidence of hypoglycemia an weight gain. 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 an antigenic 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 for diabetics. Sitagliptin 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. The active site of DPP-4 consists of a hydrophobic "S1" pocket and several hydrogen bonding residues, ideal for binding terminal dipeptides. Sitagliptin binds to the active site of DPP-4 with great specificity (DPP-4 IC50: 18 nM vs. >50,000 nM for other DPPs), situating its trifluorophenyl moiety within the S1 hydrophobic pocket, forming four hydrogen bond interactions with residues Tyr 662, Glu 205, & Glu 206, and burying its trifluoro group within a a very tight pocket formed by residues Ser 209 and Arg 358. Pharmacokinetics DPP4 Inhibitor Pharmacokinetics Parameter Vildagliptin (Galvus) Sitagliptin (Januvia) Saxagliptin (Onglyza) Tmax (hr) 1.75 1-4 2 Cmax (ng/ml) 290 330 34 Bioavailability (%) 85 87 67 Protein Binding (%) 9 38 0 T1/2 (hr) 2-3 12.4 2.5 AUC (ng/ml/hr) 1610 3470 101 IC50 (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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