SITAGLIPTIN HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C16H15F6N5O.ClH
Molecular Weight	443.775
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.N[C@@H](CC(=O)N1CCN2C(C1)=NN=C2C(F)(F)F)CC3=C(F)C=C(F)C(F)=C3

InChI

InChIKey=PNXSHNOORJKXDW-SBSPUUFOSA-N

InChI=1S/C16H15F6N5O.ClH/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;1H/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 8297		18.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 259 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021995s034lbl.pdf	Palliative		Approved 8429	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

Doses

Dose	Population	Adverse events
200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/30346099	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: https://pubmed.ncbi.nlm.nih.gov/30346099	Other AEs: Vomiting... Other AEs: Vomiting (12.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/30346099
800 mg single, oral Studied dose Dose: 800 mg Route: oral Route: single Dose: 800 mg Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021995lbl.pdf https://pubmed.ncbi.nlm.nih.gov/19602719	healthy, 18-45 years n = 77 Health Status: healthy Age Group: 18-45 years Sex: M+F Population Size: 77 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021995lbl.pdf https://pubmed.ncbi.nlm.nih.gov/19602719	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021995lbl.pdf https://pubmed.ncbi.nlm.nih.gov/19602719
1700 mg single, oral Overdose Dose: 1700 mg Route: oral Route: single Dose: 1700 mg Sources: https://pubmed.ncbi.nlm.nih.gov/22277726/	unknown, 86 years Health Status: unknown Age Group: 86 years Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/22277726/	Sources: https://pubmed.ncbi.nlm.nih.gov/22277726/

AEs

AE	Significance	Dose	Population
Vomiting	12.5%	200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/30346099	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: https://pubmed.ncbi.nlm.nih.gov/30346099

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inducer 781 inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OCT transporters 14 CYP 111 P-gp 1461 OAT3 642 CYP1A2 1524 CYP2B6 810 CYP2C8 911 CYP2C19 1478	CYP2C8 693 OAT3 339 P-gp 1537 OAT1 326 PEPT1 49 OCT2 355 OAT4 78

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no [IC50 >100 uM]
CYP3A4 1925	inhibitor 3277 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 147	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022044s000_PharmR.pdf Page: 6.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022044s000_PharmR.pdf Page: 6.0	no
OCT transporters 14	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022044s000_ClinPharmR.pdf Page: 9.0	no
P-gp 1650	inhibitor 3277 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 78	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	inconclusive
OAT1 326	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no
OCT2 355	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no
PEPT1 49	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 15.0	no
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 4, 42	yes
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 4, 42	yes
OAT3 339	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021995s000_ClinPharmR.pdf Page: 4, 15	yes
P-gp 1537	substrate 3367 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 1647	inhibitor 1626 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
MolPort	MolPort-003-666-756	https://www.molport.com/shop/molecule-link/MolPort-003-666-756
ZINC	ZINC000001489478	http://zinc15.docking.org/substances/ZINC000001489478
eMolecules	6755163	https://www.emolecules.com/cgi-bin/more?vid=6755163

PubMed

Title	Date	PubMed
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
Sitagliptin: a viewpoint by Itamar Raz.	2007	17352518
Sitagliptin: a viewpoint by Mark S. Kipnes.	2007	17352517
Sitagliptin.	2007	17352516
Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus.	2007 Apr	17940427
[Glucagon-like peptide-1 (GLP-1), new target for the treatment of type 2 diabetes].	2007 Apr	17566392
Dipeptidyl peptidase 4 inhibition with sitagliptin: a new therapy for type 2 diabetes.	2007 Apr	17371200
beta-cell failure in diabetes and preservation by clinical treatment.	2007 Apr	17353295
[Incretin enhancers, incretin mimetics: from therapeutic concept to clinical application].	2007 Apr 1	17383951
[Sitagliptin. Dipeptidylpeptidase 4 inhibitor for patients with diabetes mellitus type 2].	2007 Aug	17879807
Type 2 diabetes: the end of clinical inertia.	2007 Aug	17713297
Type 2 diabetes drug boom: is newer better?	2007 Aug	17712909
Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus.	2007 Aug	17655515
Antihyperglycaemic therapy in elderly patients with type 2 diabetes: potential role of incretin mimetics and DPP-4 inhibitors.	2007 Aug	17593275
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	17485570
Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors.	2007 Dec 15	17977724
Incretins: a new treatment option for type 2 diabetes?	2007 Feb	17379930
Sitagliptin.	2007 Feb	17342863
[New class of oral antidiabetic drugs. Effective in combination with metformin].	2007 Jan	17619359
New treatment for diabetes.	2007 Jan-Feb	17342826
Management of comorbid diabetes and cancer.	2007 Jul	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 Jul	17695659
A review of the effects of antihyperglycaemic agents on body weight: the potential of incretin targeted therapies.	2007 Jul	17559747
Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor.	2007 Jul	17468348
Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis.	2007 Jul 11	17622601
Dipeptidyl peptidase 4 (DPP-4) inhibitors and their role in Type 2 diabetes management.	2007 Jul-Aug	17848846
Janumet.	2007 Jun	17605185
Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes.	2007 Jun	17559733
Does addition of sitagliptin to metformin monotherapy improve glycemic control in patients with type 2 diabetes mellitus?	2007 Jun	17457306
Triazolopiperazine-amides as dipeptidyl peptidase IV inhibitors: close analogs of JANUVIA (sitagliptin phosphate).	2007 Jun 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 Jun 15	17433672
Treatment of type 2 diabetes mellitus and the incretin system.	2007 May	17694940
Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: focus on sitagliptin.	2007 May	17392725
New treatments for diabetes.	2007 May 24	17526096
New treatments for diabetes.	2007 May 24	17526095
New treatments for diabetes.	2007 May 24	17526094
New treatments for diabetes.	2007 May 24	17522409
[The incretin effect: a new therapeutic target in type 2 diabetes].	2007 Sep	17958029
Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.	2007 Sep	17877544
Using prandial insulin to achieve glycemic control in type 2 diabetes.	2007 Sep	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 Sep	17593236
Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers.	2007 Sep	17575559
Dose-proportionality of a final market image sitagliptin formulation, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers.	2007 Sep	17571284
Sitagliptin: a novel drug for the treatment of type 2 diabetes.	2007 Sep-Oct	17700385
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	17939170
Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes.	2008 Feb	17933414
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	17906701
Dipeptidyl peptidase IV inhibitors and diabetes therapy.	2008 Jan 1	17981665

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 HYDROCHLORIDE

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)-, MONOHYDROCHLORIDE

Systematic Name

English

1-BUTANONE, 3-AMINO-1-(5,6-DIHYDRO-3-(TRIFLUOROMETHYL)-1,2,4-TRIAZOLO(4,3-A)PYRAZIN-7(8H)-YL)-4-(2,4,5-TRIFLUOROPHENYL)-, HYDROCHLORIDE (1:1), (3R)-

Systematic Name

English

Code System Code Type Description

CAS

486459-71-6