Saxagliptin

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

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

InChI Identifier

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 ŲChemAxon Rotatable Bond Count2ChemAxon Refractivity83.99 m³·mol^-1ChemAxon Polarizability34.22 ųChemAxon 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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