Identification

Name
Tamibarotene
Accession Number
DB04942  (EXPT00376, DB03873)
Type
Small Molecule
Groups
Approved, 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
International/Other Brands
Amnoid / Tamibaro
Categories
UNII
08V52GZ3H9
CAS number
94497-51-5
Weight
Average: 351.4388
Monoisotopic: 351.183443671
Chemical Formula
C22H25NO3
InChI Key
MUTNCGKQJGXKEM-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).

TargetActionsOrganism
ARetinoic acid receptor alpha
agonist
Human
ARetinoic acid receptor beta
agonist
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

Over 99%, predominantly to serum albumin.

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
Not Available
Food Interactions
Not 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
Human Metabolome Database
HMDB15605
KEGG Drug
D01418
KEGG Compound
C12864
PubChem Compound
108143
PubChem Substance
46509039
ChemSpider
97231
BindingDB
50061625
ChEBI
32181
ChEMBL
CHEMBL25202
Therapeutic Targets Database
DAP000461
PharmGKB
PA164743464
IUPHAR
2648
Guide to Pharmacology
GtP Drug Page
HET
A80
Wikipedia
Tamibarotene
PDB Entries
2cbr

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1TerminatedTreatmentAcute Promyelocytic Leukemia (APL)1
2CompletedTreatmentAcute Promyelocytic Leukemia (APL)1
2CompletedTreatmentCrohn's Disease (CD)1
2RecruitingTreatmentLeukemia Acute Myeloid Leukemia (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

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 Solubility0.000575 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
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as tetralins. These are polycyclic aromatic compounds containing a tetralin moiety, which consists of a benzene fused to a cyclohexane.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Tetralins
Sub Class
Not Available
Direct Parent
Tetralins
Alternative Parents
Benzoic acids / Benzamides / Benzoyl derivatives / Secondary carboxylic acid amides / Monocarboxylic acids and derivatives / Carboxylic acids / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / Organic oxides
show 1 more
Substituents
Tetralin / Benzamide / Benzoic acid or derivatives / Benzoic acid / Benzoyl / Monocyclic benzene moiety / Secondary carboxylic acid amide / Carboxamide group / Monocarboxylic acid or derivatives / Carboxylic acid
show 9 more
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
retinoid, 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 expressi...
Gene Name
RARA
Uniprot ID
P10276
Uniprot Name
Retinoic acid receptor alpha
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 expressi...
Gene Name
RARB
Uniprot ID
P10826
Uniprot Name
Retinoic acid receptor beta
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
Uniprot Name
Cellular retinoic acid-binding protein 1
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 November 09, 2017 03:49