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Record Information
Version4.0
StatusExpected but not Quantified
Creation Date2012-09-06 15:16:52 UTC
Update Date2020-02-26 21:41:31 UTC
HMDB IDHMDB0015390
Secondary Accession Numbers
  • HMDB15390
Metabolite Identification
Common NameSitagliptin
DescriptionSitagliptin, also known as MK-0431 or januvia, belongs to the class of organic compounds known as beta amino acids and derivatives. These are amino acids having a (-NH2) group attached to the beta carbon atom. Sitagliptin is excreted in the milk of rats but it is not known if it would also be expressed in human breast milk. Incretins are released throughout the day and upregulated in response to meals as part of glucose homeostasis. No differences in safety and efficacy were observed in geriatric patients compared to younger patients, however caution should be used in this population as they are more likely to have reduced renal function. Sitagliptin is a very strong basic compound (based on its pKa). There is currently a lack of safety and effectiveness data in pediatric patients. The M2 metabolite is the cis isomer while the M5 metabolite is the trans isomer of the same metabolite. 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.
Structure
Data?1582753291
Synonyms
ValueSource
(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-amineChEBI
MK-0431ChEBI
SitagliptinaChEBI
SitagliptineChEBI
SitagliptinumChEBI
SitagliptanHMDB
Sitagliptin phosphateHMDB
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-amineHMDB
Anhydrous, sitagliptin phosphateHMDB
JanuviaHMDB
Monohydrate, sitagliptin monophosphateHMDB
Monohydrate, sitagliptin phosphateHMDB
monoPhosphate monohydrate, sitagliptinHMDB
Phosphate anhydrous, sitagliptinHMDB
Phosphate monohydrate, sitagliptinHMDB
Phosphate, sitagliptinHMDB
Sitagliptin monophosphate monohydrateHMDB
Sitagliptin phosphate anhydrousHMDB
Sitagliptin phosphate monohydrateHMDB
Chemical FormulaC16H15F6N5O
Average Molecular Weight407.3136
Monoisotopic Molecular Weight407.118079357
IUPAC Name(3R)-3-amino-1-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one
Traditional Namesitagliptin
CAS Registry Number486460-32-6
SMILES
N[C@@H](CC(=O)N1CCN2C(C1)=NN=C2C(F)(F)F)CC1=CC(F)=C(F)C=C1F
InChI Identifier
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
InChI KeyMFFMDFFZMYYVKS-SECBINFHSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as beta amino acids and derivatives. These are amino acids having a (-NH2) group attached to the beta carbon atom.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentBeta amino acids and derivatives
Alternative Parents
Substituents
  • Beta amino acid or derivatives
  • Amphetamine or derivatives
  • Triazolopyrazine
  • Fluorobenzene
  • Halobenzene
  • Aralkylamine
  • Aryl fluoride
  • Aryl halide
  • Monocyclic benzene moiety
  • Pyrazine
  • Benzenoid
  • 1,2,4-triazole
  • Triazole
  • Tertiary carboxylic acid amide
  • Heteroaromatic compound
  • Azole
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Organic nitrogen compound
  • Organohalogen compound
  • Primary aliphatic amine
  • Organic oxide
  • Organopnictogen compound
  • Organofluoride
  • Carbonyl group
  • Organic oxygen compound
  • Amine
  • Organonitrogen compound
  • Alkyl halide
  • Alkyl fluoride
  • Hydrocarbon derivative
  • Organooxygen compound
  • Primary amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Ontology
Disposition

Biological location:

Role

Industrial application:

Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting PointNot AvailableNot Available
Boiling PointNot AvailableNot Available
Water Solubility0.034 g/LNot Available
LogP1.5Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.034 g/LALOGPS
logP1.95ALOGPS
logP1.26ChemAxon
logS-4.1ALOGPS
pKa (Strongest Basic)8.78ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area77.04 ŲChemAxon
Rotatable Bond Count5ChemAxon
Refractivity87.49 m³·mol⁻¹ChemAxon
Polarizability32.66 ųChemAxon
Number of Rings3ChemAxon
BioavailabilityYesChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0295-2921000000-ee26b46d46fd47d93f77Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0a4i-0000900000-ce9211ae5927c697618cSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-052r-0690500000-c28779e719a0e517d106Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0076-0930000000-1337dd7fb10ab92722b5Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-00dl-0900000000-91485eb0052ad2f3637aSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-00di-0900000000-7d92431093315efaed86Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-000i-0390000000-c8853d370b51f01b194bSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0a4i-0000900000-2895dd4a879799635ae6Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-007c-0970100000-17431cd80097dff5c35fSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00dl-0910000000-29041ebd42cb7f6026dfSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00di-0900000000-dc60c3b1e5f0ba0e5e23Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0umi-0900000000-b1e1f886377c8d9b2a5dSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-004i-0900000000-d9e2b332d0ff3c6e283bSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0a4i-0000900000-3403c0e74f19a7d0832aSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-007c-0970000000-6aa1fc14d171d0102a2cSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00dl-0910000000-62ba59074d19e0d89306Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-00di-0900000000-91600010aa7e80c0e67cSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-0fmi-0900000000-d38f8b74df088a3b8232Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-004i-0900000000-08cf9f4ac284f2cd9057Spectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , positivesplash10-000i-0390000000-b6e5cd73f4ff7abd2747Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a4l-0427900000-7b4c67a1a8add9744953Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0596-0921100000-2f2b7773685fbf5f2fabSpectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0uka-3900000000-bce68660a46cc58a8e42Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-0111900000-0b915943568998cafd46Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0btl-0956400000-05e4d4efd040f50d1f3dSpectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-01tc-5910000000-603304da8956f43fb6efSpectrum
Biological Properties
Cellular Locations
  • Extracellular
  • Membrane
Biospecimen Locations
  • Blood
  • Urine
Tissue LocationsNot Available
Pathways
Normal Concentrations
BiospecimenStatusValueAgeSexConditionReferenceDetails
BloodExpected but not QuantifiedNot QuantifiedNot AvailableNot AvailableTaking drug identified by DrugBank entry DB01261 details
UrineExpected but not QuantifiedNot QuantifiedNot AvailableNot AvailableTaking drug identified by DrugBank entry DB01261 details
Abnormal Concentrations
Not Available
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDDB01261
Phenol Explorer Compound IDNot Available
FooDB IDNot Available
KNApSAcK IDNot Available
Chemspider ID3571948
KEGG Compound IDNot Available
BioCyc IDNot Available
BiGG IDNot Available
Wikipedia LinkSitagliptin
METLIN IDNot Available
PubChem Compound4369359
PDB ID715
ChEBI ID40237
Food Biomarker OntologyNot Available
VMH IDNot Available
MarkerDB ID
References
Synthesis ReferenceNot Available
Material Safety Data Sheet (MSDS)Not Available
General References
  1. Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA: Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005 Dec;78(6):675-88. [PubMed:16338283 ]
  2. Herman GA, Bergman A, Liu F, Stevens C, Wang AQ, Zeng W, Chen L, Snyder K, Hilliard D, Tanen M, Tanaka W, Meehan AG, Lasseter K, Dilzer S, Blum R, Wagner JA: Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. J Clin Pharmacol. 2006 Aug;46(8):876-86. [PubMed:16855072 ]
  3. Pratley RE, Salsali A: Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes. Curr Med Res Opin. 2007 Apr;23(4):919-31. [PubMed:17407649 ]
  4. Bergman A, Ebel D, Liu F, Stone J, Wang A, Zeng W, Chen L, Dilzer S, Lasseter K, Herman G, Wagner J, Krishna R: Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers. Biopharm Drug Dispos. 2007 Sep;28(6):315-22. [PubMed:17575559 ]
  5. Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP: Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin. 2008 Feb;24(2):489-96. doi: 10.1185/030079908X261069 . [PubMed:18182122 ]
  6. Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C: Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes. Vasc Health Risk Manag. 2008;4(4):753-68. [PubMed:19065993 ]

Enzymes

General function:
Involved in monooxygenase activity
Specific function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular weight:
57255.585
References
  1. Scheen AJ: Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab. 2010 Aug;12(8):648-58. doi: 10.1111/j.1463-1326.2010.01212.x. [PubMed:20590741 ]
General function:
Involved in monooxygenase activity
Specific function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti-cancer drug paclitaxel (taxol).
Gene Name:
CYP2C8
Uniprot ID:
P10632
Molecular weight:
55824.275
References
  1. Scheen AJ: Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab. 2010 Aug;12(8):648-58. doi: 10.1111/j.1463-1326.2010.01212.x. [PubMed:20590741 ]
General function:
Involved in serine-type endopeptidase activity
Specific function:
Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T-cell proliferation and NF- kappa-B activation in a T-cell receptor/CD3-dependent manner. Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion. In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM. May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation. When overexpressed, enhanced cell proliferation, a process inhibited by GPC3. Acts also as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones. Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline
Gene Name:
DPP4
Uniprot ID:
P27487
Molecular weight:
88277.9
References
  1. Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA: Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005 Dec;78(6):675-88. [PubMed:16338283 ]
  2. Bergman AJ, Stevens C, Zhou Y, Yi B, Laethem M, De Smet M, Snyder K, Hilliard D, Tanaka W, Zeng W, Tanen M, Wang AQ, Chen L, Winchell G, Davies MJ, Ramael S, Wagner JA, Herman GA: 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. Clin Ther. 2006 Jan;28(1):55-72. [PubMed:16490580 ]
  3. Gallwitz B: Therapies for the treatment of type 2 diabetes mellitus based on incretin action. Minerva Endocrinol. 2006 Jun;31(2):133-47. [PubMed:16682937 ]
  4. Herman GA, Bergman A, Liu F, Stevens C, Wang AQ, Zeng W, Chen L, Snyder K, Hilliard D, Tanen M, Tanaka W, Meehan AG, Lasseter K, Dilzer S, Blum R, Wagner JA: Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. J Clin Pharmacol. 2006 Aug;46(8):876-86. [PubMed:16855072 ]
  5. Miller S, St Onge EL: Sitagliptin: a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Ann Pharmacother. 2006 Jul-Aug;40(7-8):1336-43. [PubMed:16868220 ]
  6. Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP: Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin. 2008 Feb;24(2):489-96. doi: 10.1185/030079908X261069 . [PubMed:18182122 ]
  7. Pratley RE, Salsali A: Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes. Curr Med Res Opin. 2007 Apr;23(4):919-31. [PubMed:17407649 ]
  8. Lyseng-Williamson KA: Sitagliptin. Drugs. 2007;67(4):587-97. [PubMed:17352516 ]
  9. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P: 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. Diabetes Obes Metab. 2007 Sep;9(5):733-45. Epub 2007 Jun 26. [PubMed:17593236 ]
  10. Gallwitz B: Sitagliptin: Profile of a novel DPP-4 inhibitor for the treatment of type 2 diabetes. Drugs Today (Barc). 2007 Jan;43(1):13-25. [PubMed:17315049 ]
  11. Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C: Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes. Vasc Health Risk Manag. 2008;4(4):753-68. [PubMed:19065993 ]
  12. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

Transporters

General function:
Involved in ATP binding
Specific function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular weight:
141477.3
References
  1. Scheen AJ: Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab. 2010 Aug;12(8):648-58. doi: 10.1111/j.1463-1326.2010.01212.x. [PubMed:20590741 ]