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Details

Stereochemistry ABSOLUTE
Molecular Formula C16H15F6N5O.H3O4P
Molecular Weight 505.3088
Optical Activity ( - )
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of SITAGLIPTIN PHOSPHATE ANHYDROUS

SMILES

OP(O)(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=IQFYVLUXQXSJJN-SBSPUUFOSA-N
InChI=1S/C16H15F6N5O.H3O4P/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;1-5(2,3)4/h4,6,9H,1-3,5,7,23H2;(H3,1,2,3,4)/t9-;/m1./s1

HIDE SMILES / InChI

Molecular Formula C16H15F6N5O
Molecular Weight 407.3136
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Molecular Formula H3O4P
Molecular Weight 97.9952
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

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
[DPP-4 inhibition raises incretin levels].
2006 Aug
First-in-class diabetes drug approved.
2006 Dec 1
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
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.
2006 Nov 11
Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes.
2006 Oct
Oral agents for type 2 diabetes reduce HbA1c, are weight neutral.
2006 Sep
Inhibition of dipeptidyl-peptidase IV does not increase circulating IGF-1 concentrations in growing pigs.
2006 Sep
The burden of type 2 diabetes: strategies to prevent or delay onset.
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
Sitagliptin.
2007
[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
Characterization of two cyclic metabolites of sitagliptin.
2007 Apr
Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans.
2007 Apr
Type 2 diabetes: the end of clinical inertia.
2007 Aug
Type 2 diabetes drug boom: is newer better?
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
Sitagliptin.
2007 Feb
Multiple-dose administration of sitagliptin, a dipeptidyl peptidase-4 inhibitor, does not alter the single-dose pharmacokinetics of rosiglitazone in healthy subjects.
2007 Feb
Finding new treatments for diabetes--how many, how fast... how good?
2007 Feb 1
Sitagliptin: Profile of a novel DPP-4 inhibitor for the treatment of type 2 diabetes.
2007 Jan
Sitagliptin (Januvia) for type 2 diabetes.
2007 Jan 1
(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
2007 Jan 1
New treatment for diabetes.
2007 Jan-Feb
New drugs: sitagliptin phosphate, telbivudine, and panitumumab.
2007 Jan-Feb
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
Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis.
2007 Jul 11
Does addition of sitagliptin to metformin monotherapy improve glycemic control in patients with type 2 diabetes mellitus?
2007 Jun
Dipeptidyl peptidase-4 inhibitors: clinical data and clinical implications.
2007 Jun
Diabetes drug update: how 4 new options stack up.
2007 Mar
Dipeptidyl peptidase-IV inhibitors: a major new class of oral antidiabetic drug.
2007 Mar
Sitagliptin improved glycemic control and beta-cell function in type 2 diabetes.
2007 Mar-Apr
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
Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein.
2007 May
New treatments for diabetes.
2007 May 24
New treatments for diabetes.
2007 May 24
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
Sitagliptin: a novel drug for the treatment of type 2 diabetes.
2007 Sep-Oct
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 Wed Jul 05 23:25:00 UTC 2023
Edited
by admin
on Wed Jul 05 23:25:00 UTC 2023
Record UNII
494P4635I6
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
SITAGLIPTIN PHOSPHATE ANHYDROUS
Common Name English
SITAGLIPTIN PHOSPHATE ANHYDROUS COMPONENT OF JANUMET
Brand Name English
1,2,4-TRIAZOLO(4,3-A)PYRAZINE, 7-((3R)-3-AMINO-1-OXO-4-(2,4,5-TRIFLUOROPHENYL)BUTYL)-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-, PHOSPHATE (1:1)
Systematic Name English
SITAGLIPTIN MONOPHOSPHATE ANHYDROUS [MI]
Common Name English
SITAGLIPTIN MONOPHOSPHATE
MI  
Common Name English
7-((3R)-3-AMINO-4-(2,4,5-TRIFLUOROPHENYL)BUTANOYL)-3-(TRIFLUOROMETHYL)-5,6,7,8-TETRAHYDRO-1,2,4-TRIAZOLO(4,3-A)PYRAZINEMONOPHOSPHATE
Common Name English
Sitagliptin Phosphate [WHO-DD]
Common Name English
Code System Code Type Description
EPA CompTox
DTXSID10215789
Created by admin on Wed Jul 05 23:25:00 UTC 2023 , Edited by admin on Wed Jul 05 23:25:00 UTC 2023
PRIMARY
MERCK INDEX
M9960
Created by admin on Wed Jul 05 23:25:00 UTC 2023 , Edited by admin on Wed Jul 05 23:25:00 UTC 2023
PRIMARY
CAS
654671-78-0
Created by admin on Wed Jul 05 23:25:00 UTC 2023 , Edited by admin on Wed Jul 05 23:25:00 UTC 2023
PRIMARY
FDA UNII
494P4635I6
Created by admin on Wed Jul 05 23:25:00 UTC 2023 , Edited by admin on Wed Jul 05 23:25:00 UTC 2023
PRIMARY
PUBCHEM
6451150
Created by admin on Wed Jul 05 23:25:00 UTC 2023 , Edited by admin on Wed Jul 05 23:25:00 UTC 2023
PRIMARY
CAS
1269630-53-6
Created by admin on Wed Jul 05 23:25:00 UTC 2023 , Edited by admin on Wed Jul 05 23:25:00 UTC 2023
NON-SPECIFIC STOICHIOMETRY
SMS_ID
100000089174
Created by admin on Wed Jul 05 23:25:00 UTC 2023 , Edited by admin on Wed Jul 05 23:25:00 UTC 2023
PRIMARY
Related Record Type Details
SOLVATE->ANHYDROUS
PARENT -> SALT/SOLVATE
Related Record Type Details
ACTIVE MOIETY