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Sitagliptin



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
Pregnancy cat.

B(US)

Legal status

℞-only(US)

Routes Oral

Sitagliptin, previously identified as MK-0431, is a new oral hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. This enzyme-inhibiting drug is to be used either alone or in combination with metformin or a thiazolidinedione for control of type 2 diabetes mellitus. The benefit of this medicine is its lower side-effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values.

One of the big advantages of sitagliptin is that it can be taken as a pill - it does not need to be injected.


Contents

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]

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.

Mechanism

The drug works to competitively inhibit a protein/enzyme, dipeptidyl peptidase 4 (DPP-4), that results in an increased amount of active incretins (GLP-1 and GIP), reduced amount of release of glucagon (diminishes its release) and increased release of insulin (increases its synthesis and release) to restore 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 works by inhibiting the inactivation of the incretins GLP-1 and GIP by DPP-4.[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.

Sitagliptin incorporates a beta amino acid moiety that allows for a more favorable fit into the active site of DPP-4. The trifluorophenyl moiety also fits into a hydrophobic region of the active site.

See also

  • Dipeptidyl peptidase-4

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. 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. PMID 16855072.
v • d • e
Oral antidiabetic drugs and Insulin analogs (A10)
BiguanidesMetformin
SulfonylureasChlorpropamide, Glibenclamide (Glyburide), Gliclazide, Glimepiride, Glipizide, Gliquidone, Tolazamide, Tolbutamide
Alpha-glucosidase inhibitorsAcarbose, Miglitol, Voglibose
Thiazolidinediones (TZD)Pioglitazone, Rosiglitazone, Troglitazone
MeglitinidesNateglinide, Repaglinide, Mitiglinide
Dipeptidyl peptidase-4 (DPP-4) inhibitorsSaxagliptin, Sitagliptin, Vildagliptin
Glucagon-like peptide-1 analogExenatide
Insulin analogsfast acting (Insulin lispro, Insulin aspart, Insulin glulisine), intermediate-acting (NPH insulin), long acting (Insulin glargine, Insulin detemir)
v • d • e
Merck & Co., Inc.
Corporate Directors:Richard Clark · Johnnetta Cole · William Harrison · William Kelley · Rochelle Lazarus · Thomas Shenk · Anne Tatlock · Samuel Thier · Wendell Weeks · Peter Wendell
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Annual Revenue: $22.9 billion USD (2% FY 2004) · Employees: 63,000 · Stock Symbol: NYSE: MRK · Website: www.merck.com
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Sitagliptin". A list of authors is available in Wikipedia.
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