Details
Stereochemistry | RACEMIC |
Molecular Formula | C21H23N5S |
Molecular Weight | 377.506 |
Optical Activity | ( + / - ) |
Defined Stereocenters | 0 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CCC(CC)C(N1C=NC=N1)C2=CC=C(NC3=NC4=C(S3)C=CC=C4)C=C2
InChI
InChIKey=SNFYYXUGUBUECJ-UHFFFAOYSA-N
InChI=1S/C21H23N5S/c1-3-15(4-2)20(26-14-22-13-23-26)16-9-11-17(12-10-16)24-21-25-18-7-5-6-8-19(18)27-21/h5-15,20H,3-4H2,1-2H3,(H,24,25)
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/21228620Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/19120344
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21228620
Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/19120344
Talarozole (formerly R115866) is a new highly potent and selective azole derivative, which inhibits cytochrome-P450-dependent all-trans-retinoic acid catabolism by blocking the cytochrome P450 enzyme isoform CYP26, a retinoic acid hydroxylase. It is in clinical development for the treatment of psoriasis and acne. However, no local pharmacokinetic data on the diffusion behaviour of talarozole in the skin itself are available. As topical application might be an interesting alternative to oral therapy because of the reduced systemic side effects. The distribution of talarozole within the skin was investigated: 80% was located in the epidermis, while the remaining 20% was found in the dermis. The epidermal concentration of talarozole achieved after a single topical application was sufficiently high to enable the potential induction of local retinoid-like effects.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL5141 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19120344 |
4.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Palliative | Unknown Approved UseUnknown |
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Palliative | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
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80.3 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28446509 |
2.5 mg/kg single, oral dose: 2.5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
TALAROZOLE plasma | Mus musculus population: HEALTHY age: ADULT sex: MALE food status: FASTED |
AUC
Value | Dose | Co-administered | Analyte | Population |
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190 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28446509 |
2.5 mg/kg single, oral dose: 2.5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
TALAROZOLE plasma | Mus musculus population: HEALTHY age: ADULT sex: MALE food status: FASTED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28446509 |
2.5 mg/kg single, oral dose: 2.5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
TALAROZOLE plasma | Mus musculus population: HEALTHY age: ADULT sex: MALE food status: FASTED |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
5.8% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28446509 |
2.5 mg/kg single, oral dose: 2.5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
TALAROZOLE plasma | Mus musculus population: HEALTHY age: ADULT sex: MALE food status: FASTED |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
yes [IC50 0.0005 uM] | ||||
yes [IC50 0.004 uM] | ||||
yes [IC50 0.0051 uM] | ||||
yes [IC50 0.2684 uM] | ||||
yes [IC50 0.9522 uM] | ||||
yes [IC50 2.3919 uM] | ||||
yes [IC50 2.6 uM] | ||||
yes [IC50 23.1093 uM] | ||||
Sources: https://pubmed.ncbi.nlm.nih.gov/19016711/ |
yes | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/19016711/ |
yes |
PubMed
Title | Date | PubMed |
---|---|---|
Cyp26 genes a1, b1 and c1 are down-regulated in Tbx1 null mice and inhibition of Cyp26 enzyme function produces a phenocopy of DiGeorge Syndrome in the chick. | 2006 Dec 1 |
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Retinoic acid regulates sex-specific timing of meiotic initiation in mice. | 2006 Feb 21 |
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Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development. | 2007 Jan |
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CYP26 inhibitor R115866 increases retinoid signaling in intimal smooth muscle cells. | 2007 Jul |
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Gateways to clinical trials. | 2008 Jun |
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Talarozole, a selective inhibitor of P450-mediated all-trans retinoic acid for the treatment of psoriasis and acne. | 2008 Nov |
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Both all-trans retinoic acid and cytochrome P450 (CYP26) inhibitors affect the expression of vitamin A metabolizing enzymes and retinoid biomarkers in organotypic epidermis. | 2009 Aug |
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Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis. | 2009 Jan |
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The involvement of cytochrome p450 (CYP) 26 in the retinoic acid metabolism of human epidermal keratinocytes. | 2009 Mar |
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CYP26A1-specific antagonist influence on embryonic implantation, gene expression and endogenous retinoid concentration in rats. | 2010 Nov |
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CYP26B1 plays a major role in the regulation of all-trans-retinoic acid metabolism and signaling in human aortic smooth muscle cells. | 2011 |
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Small molecule inhibitors of retinoic acid 4-hydroxylase (CYP26): synthesis and biological evaluation of imidazole methyl 3-(4-(aryl-2-ylamino)phenyl)propanoates. | 2011 Apr 28 |
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Synthesis and biological evaluation of 3-(1H-imidazol- and triazol-1-yl)-2,2-dimethyl-3-[4-(naphthalen-2-ylamino)phenyl]propyl derivatives as small molecule inhibitors of retinoic acid 4-hydroxylase (CYP26). | 2011 Oct 13 |
Sample Use Guides
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19120344
Curator's Comment: There was analyzed heparin-binding epidermal growth factor-like growth factor (HB-EGF), involucrin and keratin 10 mRNA and protein levels in autocrine human keratinocyte cultures incubated for 18 h with RA or R115866 alone and with All-trans retinoic acid (RA) and R115866 (TALAROZOLE) combinations. R115866 alone had no effect on the expression of these genes. However, when R115866 was combined with low concentrations of RA, HB-EGF and involucrin expression was induced.
Unknown
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FDA ORPHAN DRUG |
365412
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NCI_THESAURUS |
C1740
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EU-Orphan Drug |
EU/3/12/1017
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DTXSID70942185
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100000177252
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9799888
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RR-99
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8964
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C90792
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TALAROZOLE
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201410-53-9
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CHEMBL459505
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851811-31-9
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DB13083
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ACTIVE MOIETY