Identification

Name
Ubenimex
Accession Number
DB03424  (EXPT00673)
Type
Small Molecule
Groups
Experimental, Investigational
Description

Ubenimex (also known as bestatin) is a competitive protease inhibitor. It is an inhibitor of aminopeptidase B, leukotriene A4 hydrolase, aminopeptidase N. It is being studied for use in the treatment of acute myelocytic leukemia.

Structure
Thumb
Synonyms
  • Bestatin
International/Other Brands
Bestatin (Nippon Kayaku, Japan)
Categories
UNII
I0J33N5627
CAS number
58970-76-6
Weight
Average: 308.3728
Monoisotopic: 308.173607266
Chemical Formula
C16H24N2O4
InChI Key
VGGGPCQERPFHOB-RDBSUJKOSA-N
InChI
InChI=1S/C16H24N2O4/c1-10(2)8-13(16(21)22)18-15(20)14(19)12(17)9-11-6-4-3-5-7-11/h3-7,10,12-14,19H,8-9,17H2,1-2H3,(H,18,20)(H,21,22)/t12-,13+,14+/m1/s1
IUPAC Name
(2S)-2-{[(2S,3R)-3-amino-1,2-dihydroxy-4-phenylbutylidene]amino}-4-methylpentanoic acid
SMILES
[H][C@@](N)(CC1=CC=CC=C1)[C@]([H])(O)C(O)=N[C@@]([H])(CC(C)C)C(O)=O

Pharmacology

Indication

An adjuvant therapy used for acute and chronic myelonous leukemia, lung cancer and nasopharyngeal cancer. It is also used to treat hypercholesterolaemia.

Pharmacodynamics
Not Available
Mechanism of action
TargetActionsOrganism
ULeukotriene A-4 hydrolaseNot AvailableHuman
UBacterial leucyl aminopeptidaseNot AvailableVibrio proteolyticus
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Ubenimex is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Ubenimex is combined with (S)-Warfarin.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Ubenimex is combined with 4-hydroxycoumarin.
AcenocoumarolThe risk or severity of bleeding can be increased when Ubenimex is combined with Acenocoumarol.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Ubenimex.
Anthrax immune globulin humanThe therapeutic efficacy of Anthrax immune globulin human can be decreased when used in combination with Ubenimex.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Ubenimex.
Bacillus calmette-guerin substrain connaught live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with Ubenimex.
Bacillus calmette-guerin substrain danish 1331 live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain danish 1331 live antigen can be decreased when used in combination with Ubenimex.
Bacillus calmette-guerin substrain tice live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain tice live antigen can be decreased when used in combination with Ubenimex.
Food Interactions
Not Available

References

Synthesis Reference

Hamao Umezawa, Takaaki Aoyagi, Tomio Takeuchi, Masa Hamada, Yoshiro Okami, "Biologically active substance, bestatin, and production thereof." U.S. Patent US4052449, issued October 04, 1977.

US4052449
General References
  1. Scornik OA, Botbol V: Bestatin as an experimental tool in mammals. Curr Drug Metab. 2001 Mar;2(1):67-85. [PubMed:11465152]
  2. Yoneda J, Saiki I, Fujii H, Abe F, Kojima Y, Azuma I: Inhibition of tumor invasion and extracellular matrix degradation by ubenimex (bestatin). Clin Exp Metastasis. 1992 Jan;10(1):49-59. [PubMed:1733647]
  3. Bauvois B, Dauzonne D: Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors: chemistry, biological evaluations, and therapeutic prospects. Med Res Rev. 2006 Jan;26(1):88-130. [PubMed:16216010]
  4. Wickstrom M, Larsson R, Nygren P, Gullbo J: Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Sci. 2011 Mar;102(3):501-8. doi: 10.1111/j.1349-7006.2010.01826.x. Epub 2011 Jan 30. [PubMed:21205077]
External Links
PubChem Compound
72172
PubChem Substance
46505598
ChemSpider
65145
BindingDB
50367209
ChEMBL
CHEMBL29292
HET
BES
Wikipedia
Ubenimex
PDB Entries
1gw6 / 1hs6 / 1txr / 1xry / 2dqm / 2ek9 / 2hpt / 2xq0 / 2yd0 / 2zof
show 18 more

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentLymphedema of the extremities1
2CompletedTreatmentPulmonary Arterial Hypertension (PAH)1
2TerminatedTreatmentPulmonary Arterial Hypertension (PAH)1
3CompletedBasic ScienceStroke, Ischemic1
3CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.841 mg/mLALOGPS
logP-1.7ALOGPS
logP-0.46ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)3.77ChemAxon
pKa (Strongest Basic)9.54ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area116.14 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity82.57 m3·mol-1ChemAxon
Polarizability32.97 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.6845
Blood Brain Barrier-0.7474
Caco-2 permeable-0.815
P-glycoprotein substrateNon-substrate0.5343
P-glycoprotein inhibitor INon-inhibitor0.9033
P-glycoprotein inhibitor IINon-inhibitor0.9167
Renal organic cation transporterNon-inhibitor0.9677
CYP450 2C9 substrateNon-substrate0.7943
CYP450 2D6 substrateNon-substrate0.8017
CYP450 3A4 substrateNon-substrate0.5757
CYP450 1A2 substrateNon-inhibitor0.9068
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.947
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8869
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9469
Ames testNon AMES toxic0.8067
CarcinogenicityNon-carcinogens0.8884
BiodegradationNot ready biodegradable0.528
Rat acute toxicity1.8987 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9992
hERG inhibition (predictor II)Non-inhibitor0.9606
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0ab9-2917000000-bfbc8526e18475632afb
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000i-0139000000-68cc530f9654794b2c47
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0ab9-1819000000-90a828fa86b21c610820

Taxonomy

Description
This compound belongs to the class of organic compounds known as hybrid peptides. These are compounds containing at least two different types of amino acids (alpha, beta, gamma, delta) linked to each other through a peptide bond.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Peptidomimetics
Sub Class
Hybrid peptides
Direct Parent
Hybrid peptides
Alternative Parents
Leucine and derivatives / N-acyl-L-alpha-amino acids / Beta amino acids and derivatives / Amphetamines and derivatives / Aralkylamines / N-acyl amines / Monosaccharides / Secondary carboxylic acid amides / Secondary alcohols / Amino acids
show 7 more
Substituents
Hybrid peptide / Leucine or derivatives / N-acyl-alpha-amino acid / N-acyl-alpha amino acid or derivatives / N-acyl-l-alpha-amino acid / Beta amino acid or derivatives / Alpha-amino acid or derivatives / Amphetamine or derivatives / Aralkylamine / Monocyclic benzene moiety
show 26 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Details
1. Leukotriene A-4 hydrolase
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Zinc ion binding
Specific Function
Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity.
Gene Name
LTA4H
Uniprot ID
P09960
Uniprot Name
Leukotriene A-4 hydrolase
Molecular Weight
69284.64 Da
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]
Kind
Protein
Organism
Vibrio proteolyticus
Pharmacological action
Unknown
General Function
Metal ion binding
Specific Function
Not Available
Gene Name
Not Available
Uniprot ID
Q01693
Uniprot Name
Bacterial leucyl aminopeptidase
Molecular Weight
54231.585 Da
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. Ocheltree SM, Shen H, Hu Y, Xiang J, Keep RF, Smith DE: Mechanisms of cefadroxil uptake in the choroid plexus: studies in wild-type and PEPT2 knockout mice. J Pharmacol Exp Ther. 2004 Feb;308(2):462-7. Epub 2003 Nov 4. [PubMed:14600253]
  4. Saito H, Terada T, Okuda M, Sasaki S, Inui K: Molecular cloning and tissue distribution of rat peptide transporter PEPT2. Biochim Biophys Acta. 1996 Apr 26;1280(2):173-7. [PubMed:8639691]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Proton-dependent oligopeptide secondary active transmembrane transporter activity
Specific Function
Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products.
Gene Name
SLC15A1
Uniprot ID
P46059
Uniprot Name
Solute carrier family 15 member 1
Molecular Weight
78805.265 Da
References
  1. Terada T, Sawada K, Irie M, Saito H, Hashimoto Y, Inui K: Structural requirements for determining the substrate affinity of peptide transporters PEPT1 and PEPT2. Pflugers Arch. 2000 Sep;440(5):679-84. [PubMed:11007306]
  2. Saito H, Okuda M, Terada T, Sasaki S, Inui K: Cloning and characterization of a rat H+/peptide cotransporter mediating absorption of beta-lactam antibiotics in the intestine and kidney. J Pharmacol Exp Ther. 1995 Dec;275(3):1631-7. [PubMed:8531138]
  3. Terada T, Saito H, Mukai M, Inui K: Characterization of stably transfected kidney epithelial cell line expressing rat H+/peptide cotransporter PEPT1: localization of PEPT1 and transport of beta-lactam antibiotics. J Pharmacol Exp Ther. 1997 Jun;281(3):1415-21. [PubMed:9190878]
  4. Sala-Rabanal M, Loo DD, Hirayama BA, Turk E, Wright EM: Molecular interactions between dipeptides, drugs and the human intestinal H+ -oligopeptide cotransporter hPEPT1. J Physiol. 2006 Jul 1;574(Pt 1):149-66. Epub 2006 Apr 20. [PubMed:16627568]
  5. Saito H, Terada T, Okuda M, Sasaki S, Inui K: Molecular cloning and tissue distribution of rat peptide transporter PEPT2. Biochim Biophys Acta. 1996 Apr 26;1280(2):173-7. [PubMed:8639691]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Peptide:proton symporter activity
Specific Function
Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides.
Gene Name
SLC15A2
Uniprot ID
Q16348
Uniprot Name
Solute carrier family 15 member 2
Molecular Weight
81782.77 Da
References
  1. Terada T, Sawada K, Irie M, Saito H, Hashimoto Y, Inui K: Structural requirements for determining the substrate affinity of peptide transporters PEPT1 and PEPT2. Pflugers Arch. 2000 Sep;440(5):679-84. [PubMed:11007306]
  2. Saito H, Terada T, Okuda M, Sasaki S, Inui K: Molecular cloning and tissue distribution of rat peptide transporter PEPT2. Biochim Biophys Acta. 1996 Apr 26;1280(2):173-7. [PubMed:8639691]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 05:34