Sitagliptin

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Sitagliptin
Systematic (IUPAC) name
(3R)-3-amino-1-[9-(trifluoromethyl)-
1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-
4-(2,4,5-trifluorophenyl)butan-1-one
Identifiers
CAS number 790712-60-6
ATC code A10BH01
PubChem 4369359
Chemical data
Formula C16H15F6N5O 
Mol. mass 407.314 g/mol
Pharmacokinetic data
Bioavailability 87%
Protein binding 38%
Metabolism Hepatic (CYP3A4- and CYP2C8-mediated)
Half life 8 to 14 hours[1]
Excretion Renal (80%)[1]
Therapeutic considerations
Licence data

EU, US
Pregnancy cat.

B(US)
Legal status

POM(UK) ℞-only(US)
Routes Oral

Sitagliptin (INN; previously identified as MK-0431, trade name Januvia) is an oral antihyperglycemic (anti-diabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. This enzyme-inhibiting drug is used either alone or in combination with other oral antihyperglycemic agents (such as metformin or a thiazolidinedione) for treatment of diabetes mellitus type 2. The benefit of this medicine is its lower side-effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values.

Contents

[edit] Adverse effects

In clinical trials, adverse effects were as common with sitagliptin (whether used alone or with metformin or pioglitazone) as they were with placebo, except for nausea and common cold-like symptoms, which were more common with sitagliptin.[2] There is no significant difference in the occurrence of hypoglycemia between placebo and sitagliptin.[2]

[edit] History

Sitagliptin was approved by the U.S. Food and Drug Administration (FDA) on October 17, 2006[3] and is marketed in the US as Januvia by Merck & Co. On April 2, 2007, the FDA approved an oral combination of sitagliptin and metformin marketed in the US as Janumet.

[edit] Mechanism

See also: Dipeptidyl peptidase-4 inhibitors

Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the incretins GLP-1 and GIP, gastrointestinal hormone that are released in response to a meal.[4] By preventing GLP-1 and GIP inactivation, GLP-1 and GIP are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas. This drives blood glucose levels towards normal. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminishes thus tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia) which is seen with some other oral hypoglycemic agents.

Sitagliptin incorporates a beta amino acid moiety that allows for a more favorable fit into the active site of DPP-4 as compared to the normal incretin substrates. The trifluorophenyl moiety also fits into a hydrophobic region of the active site.[citation needed]

[edit] See also

[edit] References

  1. ^ a b Herman G, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang A, Zeng W, Musson D, Winchell G, Davies M, Ramael S, Gottesdiener K, Wagner J (2005). "Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses.". Clin Pharmacol Ther 78 (6): 675–88. doi:10.1016/j.clpt.2005.09.002. PMID 16338283. 
  2. ^ a b Januvia Side Effects & Drug Interactions. RxList.com (2007). Retrieved on 2007-11-28.
  3. ^ U.S. Food and Drug Administration (October 17, 2006). "FDA Approves New Treatment for Diabetes". Press release. Retrieved on 2006-10-17.
  4. ^ Herman G, Bergman A, Liu F, Stevens C, Wang A, Zeng W, Chen L, Snyder K, Hilliard D, Tanen M, Tanaka W, Meehan A, Lasseter K, Dilzer S, Blum R, Wagner J (2006). "Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects.". J Clin Pharmacol 46 (8): 876–86. doi:10.1177/0091270006289850. PMID 16855072. 

[edit] External links

v • d • e
Oral antidiabetic drugs and Insulin analogs (A10)
Biguanides
Sulfonylureas
Alpha-glucosidase inhibitors
Thiazolidinediones (TZD)
Meglitinides
Dipeptidyl peptidase-4 (DPP-4) inhibitors
Alogliptin†, Saxagliptin†, Sitagliptin, Vildagliptin
Glucagon-like peptide-1 analog
Exenatide, Liraglutide†, Albiglutide†
Amylin analog
Insulin analogs
Dual PPAR agonists
SGLT2 inhibitor
Dapagliflozin†, Remogliflozin†
†Undergoing clinical trials. ‡ Withdrawn from market. §Development halted.
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