Sitagliptin Phosphate

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C16H15F6N5O.H2O.H3O4P
Molecular Weight	523.3241
Optical Activity	( - )
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O.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=GQPYTJVDPQTBQC-KLQYNRQASA-N

InChI=1S/C16H15F6N5O.H3O4P.H2O/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);1H2/t9-;;/m1../s1

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021995s034lbl.pdf
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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dipeptidyl peptidase IV 37 Target ID: CHEMBL284 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17580730	Inhibitor 8504		18.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 262 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021995s034lbl.pdf	Palliative		Approved 8583	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

C_max

Value	Dose	Co-administered	Analyte	Population
950 nM DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022044s046lbl.pdf	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 DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022044s046lbl.pdf	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
12.4 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022044s046lbl.pdf	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

F_unbound

Value	Dose	Co-administered	Analyte	Population
62% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022044s046lbl.pdf	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

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 inducer 1087 inhibitor 2252	inhibitor 2438	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OCT transporters 14 CYP 110 P-gp 1741 OAT3 747 CYP1A2 2153 CYP2B6 926 CYP2C8 1057 CYP2C19 2057	CYP2C8 810 OAT3 391 P-gp 2052 OAT1 395 PEPT1 60 OCT2 434 OAT4 93

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf 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. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15, 30
CYP 150	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022044s000_PharmR.pdf Page: 6.0	no
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022044s000_PharmR.pdf Page: 6.0	no
OCT transporters 14	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022044s000_ClinPharmR.pdf Page: 9.0	no
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf 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 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0

Drug as victim

Target	Modality	Activity	Clinical evidence
OAT4 93	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	inconclusive
OAT1 395	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no
OCT2 434	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no
PEPT1 60	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no
CYP2C8 810	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 4, 42	yes
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 4, 42	yes
OAT3 391	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 4, 15	yes
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 4, 15	yes	yes (co-administration study) Comment: cyclosporin A significantly inhibited P-gp transport of sitagliptin Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 4, 15

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_PharmR.pdf Page: 22, 23

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:40237	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:40237
ChemicalBook	CB01449778	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB01449778
eMolecules	6755163	https://www.emolecules.com/cgi-bin/more?vid=6755163
MolPort	MolPort-003-666-756	https://www.molport.com/shop/molecule-link/MolPort-003-666-756
ZINC	ZINC000001489478	http://zinc15.docking.org/substances/ZINC000001489478

PubMed

Title	Date	PubMed
Sensitive liquid chromatography tandem mass spectrometry method for the quantification of sitagliptin, a DPP-4 inhibitor, in human plasma using liquid-liquid extraction.	2008-02	17939170
Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes.	2008-02	17933414
Dipeptidyl peptidase IV inhibitors and diabetes therapy.	2008-01-01	17981665
How lithium treatment generates neutrophilia by enhancing phosphorylation of GSK-3, increasing HIF-1 levels and how this path is important during engraftment.	2008-01	17906701
Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors.	2007-12-15	17977724
Dipeptidyl peptidase 4 (DPP-4) inhibitors and their role in Type 2 diabetes management.	2007-09-13	17848846
[The incretin effect: a new therapeutic target in type 2 diabetes].	2007-09	17958029
Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.	2007-09	17877544
Using prandial insulin to achieve glycemic control in type 2 diabetes.	2007-09	17764645
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.	2007-09	17593236
Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers.	2007-09	17575559
Dose-proportionality of a final market image sitagliptin formulation, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers.	2007-09	17571284
Sitagliptin: a novel drug for the treatment of type 2 diabetes.	2007-08-19	17700385
[Sitagliptin. Dipeptidylpeptidase 4 inhibitor for patients with diabetes mellitus type 2].	2007-08	17879807
Type 2 diabetes: the end of clinical inertia.	2007-08	17713297
Type 2 diabetes drug boom: is newer better?	2007-08	17712909
Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus.	2007-08	17655515
Antihyperglycaemic therapy in elderly patients with type 2 diabetes: potential role of incretin mimetics and DPP-4 inhibitors.	2007-08	17593275
Antidiabetic medications in overweight/obese patients with type 2 diabetes: drawbacks of current drugs and potential advantages of incretin-based treatment on body weight.	2007-08	17593274
Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes.	2007-08	17485570
Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis.	2007-07-11	17622601
Management of comorbid diabetes and cancer.	2007-07	17844893
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.	2007-07	17695659
A review of the effects of antihyperglycaemic agents on body weight: the potential of incretin targeted therapies.	2007-07	17559747
[New concepts in the treatment of type 2 diabetes].	2007-07	17541529
Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor.	2007-07	17468348
Triazolopiperazine-amides as dipeptidyl peptidase IV inhibitors: close analogs of JANUVIA (sitagliptin phosphate).	2007-06-15	17434732
Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin.	2007-06-15	17433672
Sitagliptin/metformin (Janumet) for type 2 diabetes.	2007-06-04	17541377
Janumet.	2007-06	17605185
Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes.	2007-06	17559733
Does addition of sitagliptin to metformin monotherapy improve glycemic control in patients with type 2 diabetes mellitus?	2007-06	17457306
New treatments for diabetes.	2007-05-24	17526096
New treatments for diabetes.	2007-05-24	17526095
New treatments for diabetes.	2007-05-24	17526094
New treatments for diabetes.	2007-05-24	17522409
Treatment of type 2 diabetes mellitus and the incretin system.	2007-05	17694940
Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: focus on sitagliptin.	2007-05	17392725
[Incretin enhancers, incretin mimetics: from therapeutic concept to clinical application].	2007-04-01	17383951
Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus.	2007-04	17940427
[Glucagon-like peptide-1 (GLP-1), new target for the treatment of type 2 diabetes].	2007-04	17566392
Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes.	2007-04	17407649
Dipeptidyl peptidase 4 inhibition with sitagliptin: a new therapy for type 2 diabetes.	2007-04	17371200
beta-cell failure in diabetes and preservation by clinical treatment.	2007-04	17353295
Incretins: a new treatment option for type 2 diabetes?	2007-02	17379930
[New class of oral antidiabetic drugs. Effective in combination with metformin].	2007-01	17619359
The burden of type 2 diabetes: strategies to prevent or delay onset.	2007	17969381
Review of sitagliptin phosphate: a novel treatment for type 2 diabetes.	2007	17580730
Discovery of JANUVIA (Sitagliptin), a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.	2007	17352677
New therapeutic strategies for the treatment of type 2 diabetes mellitus based on incretins.	2005	17491680

Patents

Sample Use Guides

In Vivo Use Guide

100 mg once daily. It can be taken with or without food.

Route of Administration: Oral

In Vitro Use Guide

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.

Name

Type

Language

Sitagliptin Phosphate

Official Name

English

SITAGLIPTIN PHOSPHATE HYDRATE

Preferred Name

English

SITAGLIPTIN PHOSPHATE MONOHYDRATE

Common 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) MONOHYDRATE

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]pyrazine monophosphate monohydrate

Systematic Name

English

SITAGLIPTIN PHOSPHATE [MART.]

Common Name

English

SITAGLIPTIN PHOSPHATE MONOHYDRATE [EP MONOGRAPH]

Common Name

English

SITAGLIPTIN MONOPHOSPHATE MONOHYDRATE [MI]

Common Name

English

JANUVIA

Brand Name

English

SITAGLIPTIN PHOSPHATE [USP-RS]

Common Name

English

SITAGLIPTIN PHOSPHATE [ORANGE BOOK]

Common Name

English

SITAGLIPTIN MONOPHOSPHATE MONOHYDRATE

Common Name

English

SITAGLIPTIN PHOSPHATE [JAN]

Common Name

English

GLACTIV

Brand Name

English

MK-0431

Code

English

STEGLUJAN COMPONENT SITAGLIPTIN PHOSPHATE

Brand Name

English

SITAGLIPTIN PHOSPHATE HYDRATE [JAN]

Common Name

English

JANUMET COMPONENT SITAGLIPTIN PHOSPHATE

Brand Name

English

SITAGLIPTIN PHOSPHATE [USP MONOGRAPH]

Common Name

English

Sitagliptin phosphate monohydrate [WHO-DD]

Common Name

English

ONO-5435

Code

English

MK0431

Code

English

SITAGLIPTIN PHOSPHATE [USAN]

Common Name

English

SITAGLIPTIN PHOSPHATE [VANDF]

Common Name

English

STELUJAN COMPONENT SITAGLIPTIN PHOSPHATE

Brand Name

English

Classification Tree Code System Code

NCI_THESAURUS

C98086