Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C16H15F6N5O.C4H6O5 |
Molecular Weight | 541.4011 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
O[C@@H](CC(O)=O)C(O)=O.N[C@@H](CC(=O)N1CCN2C(C1)=NN=C2C(F)(F)F)CC3=C(F)C=C(F)C(F)=C3
InChI
InChIKey=ASAFEPPKGUGNEZ-AMMWVCRBSA-N
InChI=1S/C16H15F6N5O.C4H6O5/c17-10-6-12(19)11(18)4-8(10)3-9(23)5-14(28)26-1-2-27-13(7-26)24-25-15(27)16(20,21)22;5-2(4(8)9)1-3(6)7/h4,6,9H,1-3,5,7,23H2;2,5H,1H2,(H,6,7)(H,8,9)/t9-;2-/m10/s1
DescriptionCurator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/23745054
https://www.ncbi.nlm.nih.gov/pubmed/17580730
Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/23745054
https://www.ncbi.nlm.nih.gov/pubmed/17580730
Sitagliptin (MK-0431), chemically (2R)-4-Oxo-4-[3- (trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl]-1-(2,4,5-trifl uorophenyl)butan-2-amine has a very high selectivity towards DPP-4, with an IC(50) of 18 nM. There is no affinity towards other DDP enzymes (DPP- 8 and DPP-9). It has been approved for the treatment of type 2 diabetes in the USA and Europe and is registered by the name Januvia (Merck Pharmaceuticals, Whitehouse Station, NJ, USA). In healthy volunteers and in patients with type 2 diabetes of different ethnic background, the tolerability of different doses given once or twice daily is good. 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. Sitagliptin is an incretin enhancer and the first marketed medication belonging to the gliptin class. In fact, no published literature exists regarding incidence or severity of hypoglycemia when sitagliptin is used off-label in combined with insulin therapy. However, is recommended to use methods to avoid hypoglycemia when using this off-label combination. Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination. Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin
Originator
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17352677
Curator's Comment: # Merck in 1999
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL284 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17580730 |
18.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Palliative | JANUVIA Approved UseJANUVIA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1.1) Important Limitations of Use: •JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. (1.2) •JANUVIA has not been studied in patients with a history of pancreatitis. (1.2, 5.1) 1.1 Monotherapy and Combination Therapy JANUVIA® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. [See Clinical Studies (14). Launch Date2006 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
950 nM |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
SITAGLIPTIN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
8.52 μM × h |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
SITAGLIPTIN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
12.4 h |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
SITAGLIPTIN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
62% |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
SITAGLIPTIN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
200 mg single, oral Highest studied dose |
unhealthy, 14.8 years n = 8 Health Status: unhealthy Condition: type 2 diabetes mellitus Age Group: 14.8 years Sex: M+F Population Size: 8 Sources: |
Other AEs: Vomiting... |
800 mg single, oral Studied dose Dose: 800 mg Route: oral Route: single Dose: 800 mg Sources: |
healthy, 18-45 years n = 77 Health Status: healthy Age Group: 18-45 years Sex: M+F Population Size: 77 Sources: |
|
1700 mg single, oral Overdose Dose: 1700 mg Route: oral Route: single Dose: 1700 mg Sources: |
unknown, 86 years |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Vomiting | 12.5% | 200 mg single, oral Highest studied dose |
unhealthy, 14.8 years n = 8 Health Status: unhealthy Condition: type 2 diabetes mellitus Age Group: 14.8 years Sex: M+F Population Size: 8 Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 15.0 |
no [IC50 >100 uM] | |||
Page: 15.0 |
no [IC50 >100 uM] | |||
Page: 15.0 |
no [IC50 >100 uM] | |||
Page: 15.0 |
no [IC50 >100 uM] | |||
Page: 15.0 |
no [IC50 >100 uM] | |||
Page: 15.0 |
no [IC50 >100 uM] | |||
Page: 15, 30 |
no [IC50 >100 uM] | no (co-administration study) Comment: results indicated that sitagliptin was not a time-dependent inhibitor of CYP3A4; sitagliptin did not meaningfully alter the pharmacokinetics of simvastatin. Page: 15, 30 |
||
Page: 6.0 |
no | |||
Page: 15.0 |
no | |||
Page: 6.0 |
no | |||
Page: 9.0 |
no | |||
Page: 15.0 |
no | no (co-administration study) Comment: sitagliptin had no inhibitory effect on the P-gp mediated transport of digoxin, verapmil, ritonavir, adn vinblastine Page: 15.0 |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 15.0 |
inconclusive | |||
Page: 15.0 |
no | |||
Page: 15.0 |
no | |||
Page: 15.0 |
no | |||
Page: 4, 42 |
yes | |||
Page: 4, 42 |
yes | |||
Page: 4, 15 |
yes | |||
Page: 4, 15 |
yes | yes (co-administration study) Comment: cyclosporin A significantly inhibited P-gp transport of sitagliptin Page: 4, 15 |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 22, 23 |
PubMed
Title | Date | PubMed |
---|---|---|
Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus. | 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. | 2005 Dec |
|
Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. | 2006 Dec |
|
First-in-class diabetes drug approved. | 2006 Dec 1 |
|
Sitagliptin: a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. | 2006 Jul-Aug |
|
Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. | 2006 Jun |
|
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. | 2006 Nov |
|
Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. | 2006 Nov |
|
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. | 2006 Oct |
|
Oral agents for type 2 diabetes reduce HbA1c, are weight neutral. | 2006 Sep |
|
Review of sitagliptin phosphate: a novel treatment for type 2 diabetes. | 2007 |
|
Discovery of JANUVIA (Sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. | 2007 |
|
Sitagliptin: a viewpoint by Mark S. Kipnes. | 2007 |
|
[Glucagon-like peptide-1 (GLP-1), new target for the treatment of type 2 diabetes]. | 2007 Apr |
|
Type 2 diabetes drug boom: is newer better? | 2007 Aug |
|
Incretins: a new treatment option for type 2 diabetes? | 2007 Feb |
|
[New class of oral antidiabetic drugs. Effective in combination with metformin]. | 2007 Jan |
|
New drugs: sitagliptin phosphate, telbivudine, and panitumumab. | 2007 Jan-Feb |
|
Management of comorbid diabetes and cancer. | 2007 Jul |
|
[New concepts in the treatment of type 2 diabetes]. | 2007 Jul |
|
Janumet. | 2007 Jun |
|
Diabetes drug update: how 4 new options stack up. | 2007 Mar |
|
Treatment of type 2 diabetes mellitus and the incretin system. | 2007 May |
|
New treatments for diabetes. | 2007 May 24 |
|
Using prandial insulin to achieve glycemic control in type 2 diabetes. | 2007 Sep |
|
Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers. | 2007 Sep |
|
Sitagliptin: a novel drug for the treatment of type 2 diabetes. | 2007 Sep-Oct |
|
Sensitive liquid chromatography tandem mass spectrometry method for the quantification of sitagliptin, a DPP-4 inhibitor, in human plasma using liquid-liquid extraction. | 2008 Feb |
Sample Use Guides
100 mg once daily. It can be taken with or without food.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/23849976
Curator's Comment: Sitagliptin therapy enhances circulating angiogenic cell numbers, angiogenesis and blood flow in the critical limb ischemia area.
Adipose tissue from adult-male Fischer 344 rats were cultured in endothelial progenitor cell culture medium for 14 d with (25 μmol/L) or without sitagliptin.
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1240039-02-4
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163203575
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6Q9M3E3GG7
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100000166760
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ACTIVE MOIETY
SUBSTANCE RECORD