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Cilastatin

July 24, 2017
Common Name

Cilastatin Description

A renal dehydropeptidase-I and leukotriene D4 dipeptidase inhibitor. Since the antibiotic, imipenem, is hydrolyzed by dehydropeptidase-I, which resides in the brush border of the renal tublie, cilastatin is administered with imipenem to increase its effectiveness. The drug also inhibits the metabolism of leukotriene D4 to leukotriene E4. [PubChem] Structure

MOLSDF3D-SDFPDBSMILESInChI View 3D Structure

Synonyms

Value Source (L)-7-(2-amino-2-Carboxy-ethylslifanyl)-2-[(2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoic acidChEBI (Z)-(S)-6-Carboxy-6-[(S)-2,2-dimethylcyclopropanecarboxamido]hex-5-enyl-L-cysteineChEBI (Z)-7-((R)-2-amino-2-Carboxy-ethylslifanyl)-2-[((S)-2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoic acidChEBI CilastatinaChEBI CilastatineChEBI CilastatinumChEBI (L)-7-(2-amino-2-Carboxy-ethylslifanyl)-2-[(2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoateGenerator (L)-7-(2-amino-2-Carboxy-ethylsliphanyl)-2-[(2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoateGenerator (L)-7-(2-amino-2-Carboxy-ethylsliphanyl)-2-[(2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoic acidGenerator (Z)-7-((R)-2-amino-2-Carboxy-ethylslifanyl)-2-[((S)-2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoateGenerator (Z)-7-((R)-2-amino-2-Carboxy-ethylsliphanyl)-2-[((S)-2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoateGenerator (Z)-7-((R)-2-amino-2-Carboxy-ethylsliphanyl)-2-[((S)-2,2-dimethyl-cyclopropanecarbonyl)-amino]-hept-2-enoic acidGenerator Cilastatin sodiumMeSH Monosodium salt, cilastatinMeSH Salt, cilastatin monosodiumMeSH Cilastatin monosodium saltMeSH Sodium, cilastatinMeSH

Chemical Formlia

C16H26N2O5S Average Molecliar Weight

358.453 Monoisotopic Molecliar Weight

358.156242642 IUPAC Name

(2Z)-7-{[(2R)-2-amino-2-carboxyethyl]slifanyl}-2-{[(1S)-2,2-dimethylcyclopropyl]formamido}hept-2-enoic acid Traditional Name

cilastatin CAS Registry Number

82009-34-5 SMILES

N[C@@H](CSCCCCC=C(/NC(=O)[C@H]1CC1(C)C)C(=O)O)C(=O)O

InChI Identifier

InChI=1S/C16H26N2O5S/c1-16(2)8-10(16)13(19)18-12(15(22)23)6-4-3-5-7-24-9-11(17)14(20)21/h6,10-11H,3-5,7-9,17H2,1-2H3,(H,18,19)(H,20,21)(H,22,23)/b12-6-/t10-,11+/m1/s1

InChI Key

DHSUYTOATWAVLW-WFVMDLQDSA-N Chemical Taxonomy Description

This compound belongs to the class of chemical entities known as n-acyl-alpha amino acids. These are compounds containing an alpha amino acid which bears an acyl group at its terminal nitrogen atom. Kingdom

Chemical entities Super Class

Organic compounds Class

Organic acids and derivatives Sub Class

Carboxylic acids and derivatives Direct Parent

N-acyl-alpha amino acids Alternative Parents

  • L-cysteine-S-conjugates
  • L-alpha-amino acids
  • Medium-chain fatty acids
  • Unsaturated fatty acids
  • Cyclopropanecarboxylic acids and derivatives
  • Dicarboxylic acids and derivatives
  • Amino acids
  • Secondary carboxylic acid amides
  • Slifenyl compounds
  • Carboxylic acids
  • Dialkylthioethers
  • Carbonyl compounds
  • Organopnictogen compounds
  • Organic oxides
  • Hydrocarbon derivatives
  • Monoalkylamines

    • Substituents

  • N-acyl-alpha-amino acid
  • L-cysteine-s-conjugate
  • Cysteine or derivatives
  • Alpha-amino acid
  • L-alpha-amino acid
  • Medium-chain fatty acid
  • Cyclopropanecarboxylic acid or derivatives
  • Dicarboxylic acid or derivatives
  • Unsaturated fatty acid
  • Fatty acid
  • Fatty acyl
  • Amino acid
  • Carboxamide group
  • Secondary carboxylic acid amide
  • Dialkylthioether
  • Slifenyl compound
  • Carboxylic acid
  • Thioether
  • Organoslifur compound
  • Organooxygen compound
  • Organonitrogen compound
  • Organic oxygen compound
  • Primary aliphatic amine
  • Organic nitrogen compound
  • Organic oxide
  • Carbonyl group
  • Primary amine
  • Organopnictogen compound
  • Hydrocarbon derivative
  • Amine
  • Aliphatic homomonocyclic compound

    • Molecliar Framework

    Aliphatic homomonocyclic compounds External Descriptors

  • non-proteinogenic L-alpha-amino acid (CHEBI:3697 )
  • L-cysteine derivative (CHEBI:3697 )
  • organic slifide (CHEBI:3697 )
  • carboxamide (CHEBI:3697 )

    • Ontology Status

    Expected but not Quantified Origin

  • Drug

    • Biofunction

  • Protease Inhibitors

    • Application

  • Pharmaceutical

    • Cellliar locations

  • Membrane

    • Physical Properties State

    Solid Experimental Properties

    Property Value Reference Melting PointNot AvailableNot Available Boiling PointNot AvailableNot Available Water Solubility1.00e-01 g/LNot Available LogPNot AvailableNot Available

    Predicted Properties

    Property Value Source Water Solubility0.1 mg/mLALOGPS logP-0.29ALOGPS logP-1.3ChemAxon logS-3.5ALOGPS pKa (Strongest Acidic)2.53ChemAxon pKa (Strongest Basic)9.14ChemAxon Physiological Charge-1ChemAxon Hydrogen Acceptor Count6ChemAxon Hydrogen Donor Count4ChemAxon Polar Surface Area129.72 Å2ChemAxon Rotatable Bond Count11ChemAxon Refractivity92.85 m3·mol-1ChemAxon Polarizability38.28 Å3ChemAxon Number of Rings1ChemAxon Bioavailability1ChemAxon Rlie of FiveYesChemAxon Ghose FilterYesChemAxon Vebers RlieYesChemAxon MDDR-like RlieYesChemAxon

    Spectra Spectra

    Spectrum Type Description Splash Key LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-QTOF , negativesplash10-0a4i-0009000000-ef2198c6225f95e6b765View in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-QTOF , negativesplash10-004i-0092000000-f0483d6314128c99a866View in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-ITFT , negativesplash10-03fr-0089000000-e23865517b151264287cView in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-ITFT , negativesplash10-0a4i-0009000000-f94440db25517ee87789View in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-ITFT , negativesplash10-004i-0193000000-9c52bb64f789ddf44d03View in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-ITFT , negativesplash10-01t9-0890000000-a16bc40171fdaad5d00fView in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-ITFT , negativesplash10-01q9-0900000000-7f6fb4bc2c8d8b74669aView in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-ITFT , negativesplash10-001i-0900000000-f7395a558e6db43df825View in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-ITFT , negativesplash10-0a4i-0009000000-65b5dae5f837cb16f232View in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-ITFT , negativesplash10-004i-0093000000-f41454497f85c6c231e3View in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-ITFT , negativesplash10-004i-0890000000-2d4e1ce343461b9c33ffView in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-ITFT , negativesplash10-001i-0900000000-f7395a558e6db43df825View in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-ITFT , negativesplash10-03fr-0079000000-f5a7ea868a31218529fbView in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-QTOF , positivesplash10-0a4i-0009000000-afc7a1706de335756516View in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-QTOF , positivesplash10-0uxr-0292000000-fc9fdc71c26de516aa47View in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-QTOF , positivesplash10-0f89-0980000000-c7e9f3733dc9d5876f69View in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-QTOF , positivesplash10-0f89-0940000000-5e461031ed3e8be30dceView in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-ITFT , positivesplash10-0udl-0197000000-ed9524572e0f6a20cf73View in MoNA LC-MS/MS

    LC-MS/MS Spectrum – LC-ESI-ITFT , positivesplash10-0a4i-0009000000-92adcd25c03169bce114View in MoNA 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

  • 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 DB01597

  • 21059682

    • details UrineExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB01597

  • 21059682

    • details

    Abnormal Concentrations

    Not Available Associated Disorders and Diseases Disease References

    None Associated OMIM IDs

    None External Links DrugBank ID

    DB01597 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

    4940183 KEGG Compound ID

    C01675 BioCyc ID

    Not Available BiGG ID

    Not Available Wikipedia Link

    Cilastatin NuGOwiki Link

    HMDB15535 Metagene Link

    HMDB15535 METLIN ID

    Not Available PubChem Compound

    6435415 PDB ID

    Not Available ChEBI ID

    3697

    Product: Eperezolid

    References Synthesis Reference Not Available Material Safety Data Sheet (MSDS) Not Available General References
    1. Keynan S, Hooper NM, Felici A, Amicosante G, Turner AJ: The renal membrane dipeptidase (dehydropeptidase I) inhibitor, cilastatin, inhibits the bacterial metallo-beta-lactamase enzyme CphA. Antimicrob Agents Chemother. 1995 Jul;39(7):1629-31. [PubMed:7492120 ]

    Enzymes

    General function:
    Involved in metalloexopeptidase activity
    Specific function:
    Hydrolyzes a wide range of dipeptides. Implicated in the renal metabolism of glutathione and its conjugates. Converts leukotriene D4 to leukotriene E4; it may play an important role in the regulation of leukotriene activity
    Gene Name:
    DPEP1
    Uniprot ID:
    P16444
    Molecular weight:
    45673.5
    References
    1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
    2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
    3. Farrell CA, Allegretto NJ, Hitchcock MJ: Cilastatin-sensitive dehydropeptidase I enzymes from three sources all catalyze carbapenem hydrolysis and conversion of leukotriene D4 to leukotriene E4. Arch Biochem Biophys. 1987 Jul;256(1):253-9. [PubMed:3038022 ]
    4. Kumon H, Nasu Y, Ohmori H, Kodama H, Konishi Y: [Effects of cilastatin sodium, an inhibitor of dehydropeptidase-I, on human urinary peptide excretion. Patients with renal insufficiency]. Jpn J Antibiot. 1987 Sep;40(9):1571-83. [PubMed:3480361 ]
    5. Lin JH, Chen IW, Ulm EH: Dose-dependent kinetics of cilastatin in laboratory animals. Drug Metab Dispos. 1989 Jul-Aug;17(4):426-32. [PubMed:2571484 ]
    6. Richerson MA, Ambrose PG, Quintiliani R, Nightingale CH: Formulary review of the carbapenems: comparison of imipenem/cilastatin and meropenem. Conn Med. 1998 Mar;62(3):165-9. [PubMed:9573653 ]
    7. Hirota T, Nishikawa Y, Tanaka M, Igarashi T, Kitagawa H: Characterization of dehydropeptidase I in the rat lung. Eur J Biochem. 1986 Nov 3;160(3):521-5. [PubMed:3780719 ]
    8. Hirota T, Nishikawa Y, Komai T, Igarashi T, Kitagawa H: Role of dehydropeptidase-I in the metabolism of glutathione and its conjugates in the rat kidney. Res Commun Chem Pathol Pharmacol. 1987 May;56(2):235-42. [PubMed:3474745 ]
    9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
    10. Keynan S, Hooper NM, Felici A, Amicosante G, Turner AJ: The renal membrane dipeptidase (dehydropeptidase I) inhibitor, cilastatin, inhibits the bacterial metallo-beta-lactamase enzyme CphA. Antimicrob Agents Chemother. 1995 Jul;39(7):1629-31. [PubMed:7492120 ]

    Transporters

    General function:
    Involved in ion transmembrane transporter activity
    Specific function:
    Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one molecule of endogenous dicarboxylic acid (glutarate, ketoglutarate, etc). Mediates the sodium-independent uptake of 2,3-dimercapto-1-propanesulfonic acid (DMPS). Mediates the sodium-independent uptake of p- aminohippurate (PAH), ochratoxin (OTA), acyclovir (ACV), 3-azido- 3-deoxythymidine (AZT), cimetidine (CMD), 2,4-dichloro- phenoxyacetate (2,4-D), hippurate (HA), indoleacetate (IA), indoxyl sulfate (IS) and 3-carboxy-4-methyl-5-propyl-2- furanpropionate (CMPF), cidofovir, adefovir, 9-(2- phosphonylmethoxyethyl) guanine (PMEG), 9-(2- phosphonylmethoxyethyl) diaminopurine (PMEDAP) and edaravone sulfate. PAH uptake is inhibited by p- chloromercuribenzenesulphonate (PCMBS), diethyl pyrocarbonate (DEPC), sulindac, diclofenac, carprofen, glutarate and okadaic acid. PAH uptake is inhibited by benzothiazolylcysteine (BTC), S-chlorotrifluoroethylcysteine (CTFC), cysteine S-conjugates S-dichlorovinylcysteine (DCVC), furosemide, steviol, phorbol 12-myristate 13-acetate (PMA), calcium ionophore A23187, benzylpenicillin, furosemide, indomethacin, bumetamide, losartan, probenecid, phenol red, urate, and alpha-ketoglutarate
    Gene Name:
    SLC22A6
    Uniprot ID:
    Q4U2R8
    Molecular weight:
    61815.8
    References
    1. Takeda M, Narikawa S, Hosoyamada M, Cha SH, Sekine T, Endou H: Characterization of organic anion transport inhibitors using cells stably expressing human organic anion transporters. Eur J Pharmacol. 2001 May 11;419(2-3):113-20. [PubMed:11426832 ]
    2. Khamdang S, Takeda M, Shimoda M, Noshiro R, Narikawa S, Huang XL, Enomoto A, Piyachaturawat P, Endou H: Interactions of human- and rat-organic anion transporters with pravastatin and cimetidine. J Pharmacol Sci. 2004 Feb;94(2):197-202. [PubMed:14978359 ]
    General function:
    Involved in transmembrane transport
    Specific function:
    Mediates sodium-independent multispecific organic anion transport. Transport of prostaglandin E2, prostaglandin F2, tetracycline, bumetanide, estrone sulfate, glutarate, dehydroepiandrosterone sulfate, allopurinol, 5-fluorouracil, paclitaxel, L-ascorbic acid, salicylate, ethotrexate, and alpha- ketoglutarate
    Gene Name:
    SLC22A7
    Uniprot ID:
    Q9Y694
    Molecular weight:
    60025.0
    References
    1. Enomoto A, Takeda M, Shimoda M, Narikawa S, Kobayashi Y, Kobayashi Y, Yamamoto T, Sekine T, Cha SH, Niwa T, Endou H: Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors. J Pharmacol Exp Ther. 2002 Jun;301(3):797-802. [PubMed:12023506 ]

    PMID: 16959768

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