Sitagliptin
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| Sitagliptin
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| 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 | |
| ATC code | A10 |
| PubChem | |
| 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 | |
| Routes | Oral |
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Overview
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 (monotherapy) or in combination with either metformin or a thiazolidinedione for the control of type 2 diabetes mellitus. Potential benefits of this medicine include a lower incidence of side-effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose. Another potential advantages of sitagliptin is that it can be administered orally as a pill - it does not require subqutaneous injection.
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
References
- ↑ 1.0 1.1 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.
- ↑ 2.0 2.1 Januvia Side Effects & Drug Interactions. RxList.com (2007). Retrieved on 2007-11-28.
- ↑ U.S. Food and Drug Administration (October 17, 2006). FDA Approves New Treatment for Diabetes. Press release. Retrieved on 2006-10-17.
- ↑ 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.
External links
- Merck Announces FDA Acceptance of New Drug Application for JANUVIA™ - Merck press release.
- The race to get DPP-4 inhibitors to market - Forbes.com
- Merck's March Madness - Forbes.com
- Banting and Best Diabetes Centre at UT mk-0431 - Sitagliptin
- Banting and Best Diabetes Centre at UT dp_iv - About DPP-4
Oral antidiabetic drugs and Insulin analogs (A10) | |
|---|---|
| Biguanides | Metformin |
| Sulfonylureas | Chlorpropamide, Glibenclamide (Glyburide), Gliclazide, Glimepiride, Glipizide, Gliquidone, Tolazamide, Tolbutamide |
| Alpha-glucosidase inhibitors | Acarbose, Miglitol, Voglibose |
| Thiazolidinediones (TZD) | Pioglitazone, Rivoglitazone†, Rosiglitazone, Troglitazone‡ |
| Meglitinides | Nateglinide, Repaglinide, Mitiglinide |
| Dipeptidyl peptidase-4 (DPP-4) inhibitors | Alogliptin†, Saxagliptin†, Sitagliptin, Vildagliptin, Linagliptin† |
| Glucagon-like peptide-1 analog | Exenatide, Liraglutide†, Albiglutide† |
| Amylin analog | Pramlintide |
| Insulin analogs | fast acting (Insulin lispro, Insulin aspart, Insulin glulisine), long acting (Insulin glargine, Insulin detemir) |
| Dual PPAR agonists | Aleglitazar†, Muraglitazar§, Tesaglitazar§ |
| SGLT2 inhibitor | Dapagliflozin†, Remogliflozin† |
| †Undergoing clinical trials. ‡ Withdrawn from market. §Development halted. | |
Merck & Co., Inc. | |
|---|---|
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| Annual Revenue: $22.9 billion USD (profit 2% Fiscal year 2004) · Employees: 63,000 · Stock Symbol: MRK · Website: www.merck.com | |
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