Identification
NameTamibarotene
Accession NumberDB04942  (EXPT00376, DB03873)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Tamibarotene is a novel synthetic retinoid for acute promyelocytic leukaemia (APL). Tamibarotene is currently approved in Japan for treatment of recurrent APL, and is undergoing clinical trials in the United States.

Structure
Thumb
Synonyms
retinobenzoic acid
External IDs AM-80 / AM80 / NSC-608000
Product Ingredients Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AmnoidNot Available
TamibaroNot Available
Brand mixturesNot Available
Categories
UNII08V52GZ3H9
CAS number94497-51-5
WeightAverage: 351.4388
Monoisotopic: 351.183443671
Chemical FormulaC22H25NO3
InChI KeyMUTNCGKQJGXKEM-UHFFFAOYSA-N
InChI
InChI=1S/C22H25NO3/c1-21(2)11-12-22(3,4)18-13-16(9-10-17(18)21)23-19(24)14-5-7-15(8-6-14)20(25)26/h5-10,13H,11-12H2,1-4H3,(H,23,24)(H,25,26)
IUPAC Name
4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbamoyl]benzoic acid
SMILES
CC1(C)CCC(C)(C)C2=C1C=CC(NC(=O)C1=CC=C(C=C1)C(O)=O)=C2
Pharmacology
Indication

Investigated for use/treatment in leukemia (unspecified).

Structured Indications Not Available
Pharmacodynamics

Tamibarotene is a new synthetic retinoid drug recently approved for relapsed or refractory acute promyelocytic leukemia (APL) in Japan. It is a specific agonist for retinoic acid receptor alpha/beta. Compared to all-trans retinoic acid (ATRA), a natural retinoid indicated for a first-line treatment of APL, tamibarotene is chemically more stable and several times more potent as an inducer of differentiation in promyelocytic leukemia cells. In contrast to ATRA, whose plasma concentration declines considerably during daily administration, tamibarotene sustains plasma level probably due to a lower affinity for cellular retinoic acid binding protein. Furthermore, adverse side effects were milder than those of ATRA in clinical trials.

Mechanism of action

Tamibarotene is a specific agonist for retinoic acid receptor alpha/beta with possible binding to retinoid X receptors (RXR).

TargetKindPharmacological actionActionsOrganismUniProt ID
Retinoic acid receptor alphaProteinyes
agonist
HumanP10276 details
Retinoic acid receptor betaProteinyes
agonist
HumanP10826 details
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein binding

Over 99%, predominantly to serum albumin.

MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions Not Available
Food InteractionsNot Available
References
Synthesis Reference

Hisao Ekimoto, "TAMIBAROTENE CAPSULE PREPARATION." U.S. Patent US20100048708, issued February 25, 2010.

US20100048708
General References
  1. Miwako I, Kagechika H: Tamibarotene. Drugs Today (Barc). 2007 Aug;43(8):563-8. [PubMed:17925887 ]
  2. Authors unspecified: Tamibarotene: AM 80, retinobenzoic acid, Tamibaro. Drugs R D. 2004;5(6):359-62. [PubMed:15563242 ]
  3. Sanda T, Kuwano T, Nakao S, Iida S, Ishida T, Komatsu H, Shudo K, Kuwano M, Ono M, Ueda R: Antimyeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis. Leukemia. 2005 Jun;19(6):901-9. [PubMed:15843826 ]
  4. Takeuchi M: [Clinical experience with a new synthetic retinoid, tamibarotene (Am-80) for relapsed or refractory acute promyelocytic leukemia]. Gan To Kagaku Ryoho. 2006 Mar;33(3):397-401. [PubMed:16531727 ]
  5. Mizojiri K, Okabe H, Sugeno K, Misaki A, Ito M, Kominami G, Esumi Y, Takaichi M, Harada T, Seki H, Inaba A: Studies on the metabolism and disposition of the new retinoid 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl] benzoic acid. 4th communication: absorption, metabolism, excretion and plasma protein binding in various animals and man. Arzneimittelforschung. 1997 Mar;47(3):259-69. [PubMed:9105544 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
1TerminatedTreatmentAcute Promyelocytic Leukemia (APL)1
2CompletedTreatmentAcute Promyelocytic Leukemia (APL)1
2CompletedTreatmentCrohn's Disease (CD)1
2RecruitingTreatmentAcute Myeloid Leukaemias (AML) / Myelodysplastic Syndrome1
2TerminatedTreatmentStage IIIB Non-small Cell Lung Cancer With Pleural Effusion / Stage IV Non-Small Cell Lung Cancer1
2Unknown StatusTreatmentAlzheimer's Disease (AD)1
2Unknown StatusTreatmentNephritis, Lupus1
2, 3Unknown StatusTreatmentTropical Spastic Paraparesis1
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.000575 mg/mLALOGPS
logP4.99ALOGPS
logP5.35ChemAxon
logS-5.8ALOGPS
pKa (Strongest Acidic)3.69ChemAxon
pKa (Strongest Basic)-4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area66.4 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity104.38 m3·mol-1ChemAxon
Polarizability39.16 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9674
Blood Brain Barrier+0.9589
Caco-2 permeable+0.5697
P-glycoprotein substrateNon-substrate0.5279
P-glycoprotein inhibitor INon-inhibitor0.8669
P-glycoprotein inhibitor IINon-inhibitor0.7046
Renal organic cation transporterNon-inhibitor0.944
CYP450 2C9 substrateNon-substrate0.7094
CYP450 2D6 substrateNon-substrate0.8324
CYP450 3A4 substrateSubstrate0.6002
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.7524
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.6225
CYP450 3A4 inhibitorNon-inhibitor0.925
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7513
Ames testNon AMES toxic0.8459
CarcinogenicityNon-carcinogens0.7487
BiodegradationNot ready biodegradable0.9496
Rat acute toxicity2.1477 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9979
hERG inhibition (predictor II)Non-inhibitor0.9012
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of chemical entities known as tetralins. These are polycyclic aromatic compounds containing a tetralin moiety, which consists of a benzene fused to a cyclohexane.
KingdomChemical entities
Super ClassOrganic compounds
ClassBenzenoids
Sub ClassTetralins
Direct ParentTetralins
Alternative ParentsBenzoic acids / Benzamides / Benzoyl derivatives / Secondary carboxylic acid amides / Monocarboxylic acids and derivatives / Carboxylic acids / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / Organic oxides
SubstituentsTetralin / Benzamide / Benzoic acid or derivatives / Benzoic acid / Benzoyl / Monocyclic benzene moiety / Secondary carboxylic acid amide / Carboxamide group / Monocarboxylic acid or derivatives / Carboxylic acid
Molecular FrameworkAromatic homopolycyclic compounds
External Descriptorsretinoid, dicarboxylic acid monoamide, tetralins (CHEBI:32181 )

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
agonist
General Function:
Zinc ion binding
Specific Function:
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RX...
Gene Name:
RARA
Uniprot ID:
P10276
Molecular Weight:
50770.805 Da
References
  1. Miwako I, Kagechika H: Tamibarotene. Drugs Today (Barc). 2007 Aug;43(8):563-8. [PubMed:17925887 ]
  2. Sanda T, Kuwano T, Nakao S, Iida S, Ishida T, Komatsu H, Shudo K, Kuwano M, Ono M, Ueda R: Antimyeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis. Leukemia. 2005 Jun;19(6):901-9. [PubMed:15843826 ]
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  4. Jimi S, Mashima K, Matsumoto T, Hara S, Suzumiya J, Tamura K: RARalpha is a regulatory factor for Am-80-induced cell growth inhibition of hematologic malignant cells. Int J Oncol. 2007 Aug;31(2):397-404. [PubMed:17611697 ]
  5. Authors unspecified: Tamibarotene: AM 80, retinobenzoic acid, Tamibaro. Drugs R D. 2004;5(6):359-62. [PubMed:15563242 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
agonist
General Function:
Zinc ion binding
Specific Function:
Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence or presence of ho...
Gene Name:
RARB
Uniprot ID:
P10826
Molecular Weight:
50488.63 Da
References
  1. Miwako I, Kagechika H: Tamibarotene. Drugs Today (Barc). 2007 Aug;43(8):563-8. [PubMed:17925887 ]
  2. Sanda T, Kuwano T, Nakao S, Iida S, Ishida T, Komatsu H, Shudo K, Kuwano M, Ono M, Ueda R: Antimyeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis. Leukemia. 2005 Jun;19(6):901-9. [PubMed:15843826 ]
  3. Jimi S, Mashima K, Matsumoto T, Hara S, Suzumiya J, Tamura K: RARalpha is a regulatory factor for Am-80-induced cell growth inhibition of hematologic malignant cells. Int J Oncol. 2007 Aug;31(2):397-404. [PubMed:17611697 ]
  4. Authors unspecified: Tamibarotene: AM 80, retinobenzoic acid, Tamibaro. Drugs R D. 2004;5(6):359-62. [PubMed:15563242 ]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Transporter activity
Specific Function:
Cytosolic CRABPs may regulate the access of retinoic acid to the nuclear retinoic acid receptors.
Gene Name:
CRABP1
Uniprot ID:
P29762
Molecular Weight:
15565.45 Da
References
  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235 ]
Drug created on October 21, 2007 16:23 / Updated on June 11, 2017 16:40