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Details

Stereochemistry ABSOLUTE
Molecular Formula C25H24F6N6O2
Molecular Weight 554.4875
Optical Activity UNSPECIFIED
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of Sitagliptin Fenilalanil

SMILES

N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)N2CCN3C(C2)=NN=C3C(F)(F)F)CC4=C(F)C=C(F)C(F)=C4

InChI

InChIKey=FFZDVHCAHYOEPA-UZLBHIALSA-N
InChI=1S/C25H24F6N6O2/c26-17-12-19(28)18(27)10-15(17)9-16(33-23(39)20(32)8-14-4-2-1-3-5-14)11-22(38)36-6-7-37-21(13-36)34-35-24(37)25(29,30)31/h1-5,10,12,16,20H,6-9,11,13,32H2,(H,33,39)/t16-,20+/m1/s1

HIDE SMILES / InChI

Molecular Formula C25H24F6N6O2
Molecular Weight 554.4875
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 2 / 2
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

2006
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
Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus.
2005
New therapeutic strategies for the treatment of type 2 diabetes mellitus based on incretins.
2005 Summer
[DPP-4 inhibition raises incretin levels].
2006 Aug
Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers.
2006 Jan
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.
2006 Nov 11
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
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
Review of sitagliptin phosphate: a novel treatment for type 2 diabetes.
2007
Sitagliptin.
2007
Dipeptidyl peptidase 4 inhibition with sitagliptin: a new therapy for type 2 diabetes.
2007 Apr
Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans.
2007 Apr
Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus.
2007 Aug
Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors.
2007 Dec 15
Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects.
2007 Feb
[New class of oral antidiabetic drugs. Effective in combination with metformin].
2007 Jan
Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes.
2007 Jan
[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
Janumet.
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
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial.
2007 Mar
Dipeptidyl peptidase-IV inhibitors: a major new class of oral antidiabetic drug.
2007 Mar
New treatments for diabetes.
2007 May 24
New treatments for diabetes.
2007 May 24
New treatments for diabetes.
2007 May 24
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 Sat Dec 16 19:30:46 GMT 2023
Edited
by admin
on Sat Dec 16 19:30:46 GMT 2023
Record UNII
LR99Q6X62V
Record Status Validated (UNII)
Record Version
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Name Type Language
Sitagliptin Fenilalanil
INN  
Official Name English
(2S)-2-amino-N-{(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-yl}-3-phenylpropanamide
Systematic Name English
(αS)-α-Amino-N-[(1R)-3-[5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-oxo-1-[(2,4,5-trifluorophenyl)methyl]propyl]benzenepropanamide
Systematic Name English
Benzenepropanamide, α-amino-N-[(1R)-3-[5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-3-oxo-1-[(2,4,5-trifluorophenyl)methyl]propyl]-, (αS)-
Systematic Name English
sitagliptin fenilalanil [INN]
Common Name English
Code System Code Type Description
PUBCHEM
164886617
Created by admin on Sat Dec 16 19:30:46 GMT 2023 , Edited by admin on Sat Dec 16 19:30:46 GMT 2023
PRIMARY
SMS_ID
300000047415
Created by admin on Sat Dec 16 19:30:46 GMT 2023 , Edited by admin on Sat Dec 16 19:30:46 GMT 2023
PRIMARY
INN
12357
Created by admin on Sat Dec 16 19:30:46 GMT 2023 , Edited by admin on Sat Dec 16 19:30:46 GMT 2023
PRIMARY
NCI_THESAURUS
C190468
Created by admin on Sat Dec 16 19:30:46 GMT 2023 , Edited by admin on Sat Dec 16 19:30:46 GMT 2023
PRIMARY
FDA UNII
LR99Q6X62V
Created by admin on Sat Dec 16 19:30:46 GMT 2023 , Edited by admin on Sat Dec 16 19:30:46 GMT 2023
PRIMARY
CAS
1339955-03-1
Created by admin on Sat Dec 16 19:30:46 GMT 2023 , Edited by admin on Sat Dec 16 19:30:46 GMT 2023
PRIMARY
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