Saxagliptin

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Saxagliptin, better known as Onglyza, (3bjm)

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.[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 . 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 within a tunnel capable of binding incretin compounds and situating their N-terminus in the active site.[3] This active site contains several 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. 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]

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

References

  1. Wesley UV, McGroarty M, Homoyouni A. Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway. Cancer Res. 2005 Feb 15;65(4):1325-34. PMID:15735018 doi:10.1158/0008-5472.CAN-04-1852
  2. Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int J Clin Pract. 2006 Nov;60(11):1454-70. PMID:17073841 doi:10.1111/j.1742-1241.2006.01178.x
  3. Kim D, Wang L, Beconi M, Eiermann GJ, Fisher MH, He H, Hickey GJ, Kowalchick JE, Leiting B, Lyons K, Marsilio F, McCann ME, Patel RA, Petrov A, Scapin G, Patel SB, Roy RS, Wu JK, Wyvratt MJ, Zhang BB, Zhu L, Thornberry NA, Weber AE. (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin -7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005 Jan 13;48(1):141-51. PMID:15634008 doi:10.1021/jm0493156
  4. Metzler WJ, Yanchunas J, Weigelt C, Kish K, Klei HE, Xie D, Zhang Y, Corbett M, Tamura JK, He B, Hamann LG, Kirby MS, Marcinkeviciene J. Involvement of DPP-IV catalytic residues in enzyme-saxagliptin complex formation. Protein Sci. 2008 Feb;17(2):240-50. PMID:18227430 doi:17/2/240


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