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Saxagliptin

July 24, 2017
Common Name

Saxagliptin Description

Saxagliptin (rINN), previously identified as BMS-477118, is a new oral hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. It was developed by Bristol-Myers Squibb. A New Drug Application for saxagliptin in the treatment of type 2 diabetes was submitted to the FDA in June 2008. It was based on a drug development program with 8 randomized trials: 1 phase 2 dose-ranging (2.5 – 100 mg/d) study; 6 phase 3, 24-week controlled trials with additional controlled follow-up from 12 to 42 months, double-blinded throughout; and one 12-week mechanism-of-action trial with a 2-year follow-up period. In June 2008, it was announced that Onglyza wolid be the trade name under which saxagliptin will be marketed. Structure

MOLSDF3D-SDFPDBSMILESInChI View 3D Structure

Synonyms

Value Source (1S,3S,5S)-2-((2S)-amino(3-hydroxytricyclo(3.3.1.13,7)Dec-1-yl)acetyl)-2-azabicyclo(3.1.0)hexane-3-carbonitrileChEBI BMS 477118ChEBI BMS-477118ChEBI OnglyzaHMDB 3-Hydroxyadamantylglycine-4,5-methanoprolinenitrile hydrateMeSH

Chemical Formlia

C18H25N3O2 Average Molecliar Weight

315.41 Monoisotopic Molecliar Weight

315.194677059 IUPAC Name

(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile Traditional Name

saxagliptin CAS Registry Number

361442-04-8 SMILES

N[C@H](C(=O)N1[C@H]2C[C@H]2C[C@H]1C#N)C12CC3CC(CC(O)(C3)C1)C2

InChI Identifier

InChI=1S/C18H25N3O2/c19-8-13-2-12-3-14(12)21(13)16(22)15(20)17-4-10-1-11(5-17)7-18(23,6-10)9-17/h10-15,23H,1-7,9,20H2/t10?,11?,12-,13+,14+,15-,17?,18?/m1/s1

InChI Key

QGJUIPDUBHWZPV-SGTAVMJGSA-N Chemical Taxonomy Description

This compound belongs to the class of chemical entities known as alpha amino acid amides. These are amide derivatives of alpha amino acids. Kingdom

Chemical entities Super Class

Organic compounds Class

Organic acids and derivatives Sub Class

Carboxylic acids and derivatives Direct Parent

Alpha amino acid amides Alternative Parents

  • N-acylpiperidines
  • N-acylpyrrolidines
  • Tertiary carboxylic acid amides
  • Tertiary alcohols
  • Cyclic alcohols and derivatives
  • Nitriles
  • Azacyclic compounds
  • Organopnictogen compounds
  • Organic oxides
  • Monoalkylamines
  • Hydrocarbon derivatives
  • Carbonyl compounds

    • Substituents

  • Alpha-amino acid amide
  • N-acyl-piperidine
  • N-acylpyrrolidine
  • Piperidine
  • Cyclic alcohol
  • Pyrrolidine
  • Tertiary carboxylic acid amide
  • Tertiary alcohol
  • Carboxamide group
  • Carbonitrile
  • Nitrile
  • Azacycle
  • Organoheterocyclic compound
  • Organonitrogen compound
  • Alcohol
  • Hydrocarbon derivative
  • Organic oxide
  • Primary aliphatic amine
  • Organopnictogen compound
  • Organic oxygen compound
  • Carbonyl group
  • Organooxygen compound
  • Organic nitrogen compound
  • Primary amine
  • Amine
  • Aliphatic heteropolycyclic compound

    • Molecliar Framework

    Aliphatic heteropolycyclic compounds External Descriptors

  • tertiary alcohol (CHEBI:71272 )
  • azabicycloalkane (CHEBI:71272 )
  • monocarboxylic acid amide (CHEBI:71272 )
  • adamantanes (CHEBI:71272 )
  • nitrile (CHEBI:71272 )

    • Ontology Status

    Expected but not Quantified Origin

  • Drug

    • Biofunction

    Not Available Application

  • Pharmaceutical

    • Cellliar locations

  • Extracellliar
  • Membrane

    • Physical Properties State

    Solid Experimental Properties

    Property Value Reference Melting PointNot AvailableNot Available Boiling PointNot AvailableNot Available Water SolubilityNot AvailableNot Available LogPNot AvailableNot Available

    Predicted Properties

    Property Value Source Water Solubility2.26 mg/mLALOGPS logP0.88ALOGPS logP-0.08ChemAxon logS-2.1ALOGPS pKa (Strongest Acidic)14.74ChemAxon pKa (Strongest Basic)7.9ChemAxon Physiological Charge1ChemAxon Hydrogen Acceptor Count4ChemAxon Hydrogen Donor Count2ChemAxon Polar Surface Area90.35 Å2ChemAxon Rotatable Bond Count2ChemAxon Refractivity83.99 m3·mol-1ChemAxon Polarizability34.22 Å3ChemAxon Number of Rings5ChemAxon Bioavailability1ChemAxon Rlie of FiveYesChemAxon Ghose FilterYesChemAxon Vebers RlieYesChemAxon MDDR-like RlieYesChemAxon

    Spectra Spectra

    Spectrum Type Description Splash Key Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 10V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 20V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 40V, PositiveNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 10V, NegativeNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 20V, NegativeNot Available Predicted LC-MS/MS

    Predicted LC-MS/MS Spectrum – 40V, NegativeNot Available

    Biological Properties Cellliar Locations

  • Extracellliar
  • Membrane

    • Biofluid Locations

  • Blood
  • Urine

    • Tissue Location

    Not Available Pathways

    Not Available Normal Concentrations

    Biofluid Status Value Age Sex Condition Reference Details BloodExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB06335

  • 21059682

    • details UrineExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB06335

  • 21059682

    • details

    Abnormal Concentrations

    Not Available Associated Disorders and Diseases Disease References

    None Associated OMIM IDs

    None External Links DrugBank ID

    DB06335 DrugBank Metabolite ID

    Not Available Phenol Explorer Compound ID

    Not Available Phenol Explorer Metabolite ID

    Not Available FoodDB ID

    Not Available KNApSAcK ID

    Not Available Chemspider ID

    9419005 KEGG Compound ID

    Not Available BioCyc ID

    Not Available BiGG ID

    Not Available Wikipedia Link

    Saxagliptin NuGOwiki Link

    HMDB15634 Metagene Link

    HMDB15634 METLIN ID

    Not Available PubChem Compound

    11243969 PDB ID

    Not Available ChEBI ID

    460723

    Product: Bismuth Subsalicylate

    References Synthesis Reference Not Available Material Safety Data Sheet (MSDS) Not Available General References
    1. Barnett A: DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Int J Clin Pract. 2006 Nov;60(11):1454-70. [PubMed:17073841 ]
    2. Crepaldi G, Carruba M, Comaschi M, Del Prato S, Frajese G, Paolisso G: Dipeptidyl peptidase 4 (DPP-4) inhibitors and their role in Type 2 diabetes management. J Endocrinol Invest. 2007 Jul-Aug;30(7):610-4. [PubMed:17848846 ]
    3. Metzler WJ, Yanchunas J, Weigelt C, Kish K, Klei HE, Xie D, Zhang Y, Corbett M, Tamura JK, He B, Hamann LG, Kirby MS, Marcinkeviciene J: Involvement of DPP-IV catalytic residues in enzyme-saxagliptin complex formation. Protein Sci. 2008 Feb;17(2):240-50. doi: 10.1110/ps.073253208. [PubMed:18227430 ]
    4. Rosenstock J, Sankoh S, List JF: Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab. 2008 May;10(5):376-86. doi: 10.1111/j.1463-1326.2008.00876.x. Epub 2008 Mar 18. [PubMed:18355324 ]
    5. Golightly LK, Drayna CC, McDermott MT: Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin Pharmacokinet. 2012 Aug 1;51(8):501-14. doi: 10.2165/11632930-000000000-00000. [PubMed:22686547 ]
    6. Ali S, Fonseca V: Saxagliptin overview: special focus on safety and adverse effects. Expert Opin Drug Saf. 2013 Jan;12(1):103-9. doi: 10.1517/14740338.2013.741584. Epub 2012 Nov 9. [PubMed:23137182 ]
    7. Russell S: Incretin-based therapies for type 2 diabetes mellitus: a review of direct comparisons of efficacy, safety and patient satisfaction. Int J Clin Pharm. 2013 Apr;35(2):159-72. doi: 10.1007/s11096-012-9729-9. Epub 2012 Dec 22. [PubMed:23263796 ]

    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. Upreti VV, Boulton DW, Li L, Ching A, Su H, Lacreta FP, Patel CG: Effect of rifampicin on the pharmacokinetics and pharmacodynamics of saxagliptin, a dipeptidyl peptidase-4 inhibitor, in healthy subjects. Br J Clin Pharmacol. 2011 Jul;72(1):92-102. doi: 10.1111/j.1365-2125.2011.03937.x. [PubMed:21651615 ]
    2. Patel CG, Kornhauser D, Vachharajani N, Komoroski B, Brenner E, Handschuh del Corral M, Li L, Boulton DW: Saxagliptin, a potent, selective inhibitor of DPP-4, does not alter the pharmacokinetics of three oral antidiabetic drugs (metformin, glyburide or pioglitazone) in healthy subjects. Diabetes Obes Metab. 2011 Jul;13(7):604-14. doi: 10.1111/j.1463-1326.2011.01381.x. [PubMed:21332626 ]
    3. Scheen AJ: Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions. Clin Pharmacokinet. 2010 Sep;49(9):573-88. doi: 10.2165/11532980-000000000-00000. [PubMed:20690781 ]
    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.
    Gene Name:
    CYP3A5
    Uniprot ID:
    P20815
    Molecular weight:
    57108.065
    References
    1. Upreti VV, Boulton DW, Li L, Ching A, Su H, Lacreta FP, Patel CG: Effect of rifampicin on the pharmacokinetics and pharmacodynamics of saxagliptin, a dipeptidyl peptidase-4 inhibitor, in healthy subjects. Br J Clin Pharmacol. 2011 Jul;72(1):92-102. doi: 10.1111/j.1365-2125.2011.03937.x. [PubMed:21651615 ]
    2. Patel CG, Kornhauser D, Vachharajani N, Komoroski B, Brenner E, Handschuh del Corral M, Li L, Boulton DW: Saxagliptin, a potent, selective inhibitor of DPP-4, does not alter the pharmacokinetics of three oral antidiabetic drugs (metformin, glyburide or pioglitazone) in healthy subjects. Diabetes Obes Metab. 2011 Jul;13(7):604-14. doi: 10.1111/j.1463-1326.2011.01381.x. [PubMed:21332626 ]
    3. Scheen AJ: Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions. Clin Pharmacokinet. 2010 Sep;49(9):573-88. doi: 10.2165/11532980-000000000-00000. [PubMed:20690781 ]
    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. Augeri DJ, Robl JA, Betebenner DA, Magnin DR, Khanna A, Robertson JG, Wang A, Simpkins LM, Taunk P, Huang Q, Han SP, Abboa-Offei B, Cap M, Xin L, Tao L, Tozzo E, Welzel GE, Egan DM, Marcinkeviciene J, Chang SY, Biller SA, Kirby MS, Parker RA, Hamann LG: Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005 Jul 28;48(15):5025-37. [PubMed:16033281 ]

    PMID: 23690576

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