U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C16H15F6N5O
Molecular Weight 407.3142
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of SITAGLIPTIN

SMILES

C1Cn2c(CN1C(=O)C[C@@]([H])(Cc3cc(c(cc3F)F)F)N)nnc2C(F)(F)F

InChI

InChIKey=MFFMDFFZMYYVKS-SECBINFHSA-N
InChI=1S/C16H15F6N5O/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/h4,6,9H,1-3,5,7,23H2/t9-/m1/s1

HIDE SMILES / InChI

Molecular Formula C16H15F6N5O
Molecular Weight 407.3142
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
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

Curator's Comment:: # Merck in 1999

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
18.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Palliative
JANUVIA

Approved Use

JANUVIA 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 Date

1.16095674E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
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

AUC

ValueDoseCo-administeredAnalytePopulation
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

T1/2

ValueDoseCo-administeredAnalytePopulation
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

Funbound

ValueDoseCo-administeredAnalytePopulation
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

Doses

DosePopulationAdverse events​
200 mg single, oral
Highest studied dose
Dose: 200 mg
Route: oral
Route: single
Dose: 200 mg
Sources:
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...
Other AEs:
Vomiting (12.5%)
Sources:
800 mg single, oral
Studied dose
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
Health Status: unknown
Age Group: 86 years
Sex: F
Sources:
AEs

AEs

AESignificanceDosePopulation
Vomiting 12.5%
200 mg single, oral
Highest studied dose
Dose: 200 mg
Route: oral
Route: single
Dose: 200 mg
Sources:
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:
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no [IC50 >100 uM]
no [IC50 >100 uM]
no [IC50 >100 uM]
no [IC50 >100 uM]
no [IC50 >100 uM]
no [IC50 >100 uM]
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
no
no
no
no
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 victimTox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
New therapeutic strategies for the treatment of type 2 diabetes mellitus based on incretins.
2005 Summer
The burden of type 2 diabetes: strategies to prevent or delay onset.
2007
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 Itamar Raz.
2007
Sitagliptin: a viewpoint by Mark S. Kipnes.
2007
Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus.
2007 Apr
[Glucagon-like peptide-1 (GLP-1), new target for the treatment of type 2 diabetes].
2007 Apr
Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes.
2007 Apr
[Sitagliptin. Dipeptidylpeptidase 4 inhibitor for patients with diabetes mellitus type 2].
2007 Aug
Type 2 diabetes: the end of clinical inertia.
2007 Aug
Type 2 diabetes drug boom: is newer better?
2007 Aug
Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus.
2007 Aug
Antihyperglycaemic therapy in elderly patients with type 2 diabetes: potential role of incretin mimetics and DPP-4 inhibitors.
2007 Aug
Antidiabetic medications in overweight/obese patients with type 2 diabetes: drawbacks of current drugs and potential advantages of incretin-based treatment on body weight.
2007 Aug
Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes.
2007 Aug
Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors.
2007 Dec 15
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 treatment for diabetes.
2007 Jan-Feb
Management of comorbid diabetes and cancer.
2007 Jul
New medications help those with diabetes avoid heart trouble. Drugs mimic the body's natural insulin and glucose controls, but diet and exercise are still keys to controlling the disease.
2007 Jul
A review of the effects of antihyperglycaemic agents on body weight: the potential of incretin targeted therapies.
2007 Jul
[New concepts in the treatment of type 2 diabetes].
2007 Jul
Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor.
2007 Jul
Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis.
2007 Jul 11
Dipeptidyl peptidase 4 (DPP-4) inhibitors and their role in Type 2 diabetes management.
2007 Jul-Aug
Janumet.
2007 Jun
Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes.
2007 Jun
Does addition of sitagliptin to metformin monotherapy improve glycemic control in patients with type 2 diabetes mellitus?
2007 Jun
Triazolopiperazine-amides as dipeptidyl peptidase IV inhibitors: close analogs of JANUVIA (sitagliptin phosphate).
2007 Jun 15
Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin.
2007 Jun 15
Sitagliptin/metformin (Janumet) for type 2 diabetes.
2007 Jun 4
Treatment of type 2 diabetes mellitus and the incretin system.
2007 May
Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: focus on sitagliptin.
2007 May
New treatments for diabetes.
2007 May 24
New treatments for diabetes.
2007 May 24
New treatments for diabetes.
2007 May 24
New treatments for diabetes.
2007 May 24
[The incretin effect: a new therapeutic target in type 2 diabetes].
2007 Sep
Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.
2007 Sep
Using prandial insulin to achieve glycemic control in type 2 diabetes.
2007 Sep
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin.
2007 Sep
Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers.
2007 Sep
Dose-proportionality of a final market image sitagliptin formulation, 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
Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes.
2008 Feb
How lithium treatment generates neutrophilia by enhancing phosphorylation of GSK-3, increasing HIF-1 levels and how this path is important during engraftment.
2008 Jan
Dipeptidyl peptidase IV inhibitors and diabetes therapy.
2008 Jan 1
Patents

Sample Use Guides

100 mg once daily. It can be taken with or without food.
Route of Administration: Oral
In Vitro Use Guide
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.
Substance Class Chemical
Created
by admin
on Fri Jun 25 20:33:32 UTC 2021
Edited
by admin
on Fri Jun 25 20:33:32 UTC 2021
Record UNII
QFP0P1DV7Z
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
SITAGLIPTIN
EMA EPAR   HSDB   INN   MI   VANDF   WHO-DD  
INN  
Official Name English
(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
Systematic Name English
SITAGLIPTIN [INN]
Common Name English
SITAGLIPTIN [EMA EPAR]
Common Name English
SITAGLIPTIN [WHO-DD]
Common Name English
SITAGLIPTIN [HSDB]
Common Name English
SITAGLIPTIN [MI]
Common Name English
LEZ-763
Code English
1,2,4-TRIAZOLO(4,3-A)PYRAZINE-7(8H)-PROPANAMINE, 5,6-DIHYDRO-.GAMMA.-OXO-3-(TRIFLUOROMETHYL)-.ALPHA.-((2,4,5-TRIFLUOROPHENYL)METHYL)-, (.ALPHA.R)-
Common Name English
LEZ763
Code English
SITAGLIPTIN [VANDF]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C98086
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
WHO-VATC QA10BD12
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
WHO-VATC QA10BH51
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
NDF-RT N0000175913
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
WHO-ATC A10BH51
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
WHO-ATC A10BD07
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
NDF-RT N0000175912
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
WHO-ATC A10BD24
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
LIVERTOX 890
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
WHO-ATC A10BH01
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
WHO-VATC QA10BD07
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
WHO-VATC QA10BH01
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
WHO-ATC A10BD12
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
Code System Code Type Description
CAS
486460-32-6
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
FDA UNII
QFP0P1DV7Z
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
NCI_THESAURUS
C73838
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
EPA CompTox
486460-32-6
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
INN
8692
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
LACTMED
Sitagliptin
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
HSDB
7516
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
ChEMBL
CHEMBL1422
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
EVMPD
SUB25227
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
PUBCHEM
4369359
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
MESH
C496398
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
RXCUI
593411
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY RxNorm
WIKIPEDIA
SITAGLIPTIN
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
IUPHAR
6286
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
DRUG BANK
DB01261
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
MERCK INDEX
M9960
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY Merck Index
DRUG CENTRAL
2448
Created by admin on Fri Jun 25 20:33:32 UTC 2021 , Edited by admin on Fri Jun 25 20:33:32 UTC 2021
PRIMARY
Related Record Type Details
METABOLIC ENZYME -> SUBSTRATE
TRANSPORTER -> INHIBITOR
EXCRETED UNCHANGED
AMOUNT EXCRETED
URINE
TARGET -> INHIBITOR
SALT/SOLVATE -> PARENT
BINDER->LIGAND
BINDING
SALT/SOLVATE -> PARENT
TRANSPORTER -> SUBSTRATE
SALT/SOLVATE -> PARENT
SALT/SOLVATE -> PARENT
Related Record Type Details
METABOLITE -> PARENT
MINOR
PLASMA
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Biological Half-life PHARMACOKINETIC ORAL ADMINISTRATION

SINGLE DOSE

Volume of Distribution PHARMACOKINETIC INTRAVENOUS ADMINISTRATION

SINGLE DOSE

Tmax PHARMACOKINETIC DOSE

ORAL ADMINISTRATION