T3DB: Telithromycin

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (6)XML

Targets (6)

Record Information

Version

2.0

Creation Date

2009-07-30 17:59:10 UTC

Update Date

2014-12-24 20:26:08 UTC

Accession Number

T3D3536

Identification

Common Name

Telithromycin

Class

Small Molecule

Description

Telithromycin, a semi-synthetic erythromycin derivative, belongs to a new chemical class of antibiotics called ketolides. Ketolides have been recently added to the macrolide-lincosamide-streptogramin class of antibiotics. Similar to the macrolide antibiotics, telithromycin prevents bacterial growth by interfering with bacterial protein synthesis. Telithromycin binds to the 50S subunit of the 70S bacterial ribosome and blocks further peptide elongation. Binding occurs simultaneously at to two domains of 23S RNA of the 50S ribosomal subunit, domain II and V, where older macrolides bind only to one. It is used to treat mild to moderate respiratory infections.

Compound Type

Amine
Anti-Bacterial Agent
Drug
Ester
Ether
Ketolide
Metabolite
Organic Compound
Synthetic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
Ketek

Chemical Formula

C₄₃H₆₅N₅O₁₀

Average Molecular Mass

812.004 g/mol

Monoisotopic Mass

811.473 g/mol

CAS Registry Number

191114-48-4

IUPAC Name

(3aR,4S,7R,9R,10R,11R,13R,15R,15aR)-10-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-1-{4-[4-(pyridin-3-yl)-1H-imidazol-1-yl]butyl}-tetradecahydro-1H-oxacyclotetradeca[4,3-d][1,3]oxazole-2,6,8,14-tetrone

Traditional Name

telithromycin

SMILES

[H][C@]12N(CCCCN3C=NC(=C3)C3=CN=CC=C3)C(=O)O[C@@]1(C)[C@]([H])(CC)OC(=O)[C@]([H])(C)C(=O)[C@]([H])(C)[C@@]([H])(O[C@]1([H])O[C@]([H])(C)C[C@]([H])(N(C)C)[C@@]1([H])O)[C@@](C)(C[C@@]([H])(C)C(=O)[C@]2([H])C)OC

InChI Identifier

InChI=1S/C43H65N5O10/c1-12-33-43(8)37(48(41(53)58-43)19-14-13-18-47-23-31(45-24-47)30-16-15-17-44-22-30)27(4)34(49)25(2)21-42(7,54-11)38(28(5)35(50)29(6)39(52)56-33)57-40-36(51)32(46(9)10)20-26(3)55-40/h15-17,22-29,32-33,36-38,40,51H,12-14,18-21H2,1-11H3/t25-,26-,27+,28+,29-,32+,33+,36-,37-,38-,40+,42-,43+/m1/s1

InChI Key

InChIKey=LJVAJPDWBABPEJ-RMNISARHSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as aminoglycosides. These are molecules or a portion of a molecule composed of amino-modified sugars.

Kingdom

Organic compounds

Super Class

Organic oxygen compounds

Class

Organooxygen compounds

Sub Class

Carbohydrates and carbohydrate conjugates

Direct Parent

Aminoglycosides

Alternative Parents

Substituents

Aminoglycoside core
N-substituted imidazole
Oxane
Oxazolidinone
Pyridine
1,3-dicarbonyl compound
Oxazolidine
Azole
Heteroaromatic compound
Carbamic acid ester
Imidazole
Tertiary aliphatic amine
Tertiary amine
Secondary alcohol
Lactone
Carbonic acid derivative
Amino acid or derivatives
Carboxylic acid ester
Cyclic ketone
Ketone
1,2-aminoalcohol
Acetal
Carboxylic acid derivative
Oxacycle
Dialkyl ether
Ether
Azacycle
Organoheterocyclic compound
Monocarboxylic acid or derivatives
Carbonyl group
Organic nitrogen compound
Alcohol
Amine
Organopnictogen compound
Organic oxide
Organonitrogen compound
Hydrocarbon derivative
Aromatic heteropolycyclic compound

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

Not Available

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Cytoplasm
Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Name	SMPDB Link	KEGG Link
Telithromycin Pathway	Not Available	Not Available

Applications

Not Available

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	176-188°C
Boiling Point	Not Available
Solubility	300 mg/L
LogP	3

Predicted Properties

Property	Value	Source
Water Solubility	0.028 g/L	ALOGPS
logP	4	ALOGPS
logP	5.37	ChemAxon
logS	-4.5	ALOGPS
pKa (Strongest Acidic)	8.84	ChemAxon
pKa (Strongest Basic)	7.65	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	11	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	171.85 Å²	ChemAxon
Rotatable Bond Count	11	ChemAxon
Refractivity	214.68 m³·mol⁻¹	ChemAxon
Polarizability	89.27 Å³	ChemAxon
Number of Rings	5	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_1) - 70eV, Positive	Not Available	2021-10-19	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_2) - 70eV, Positive	Not Available	2021-10-19	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_3) - 70eV, Positive	Not Available	2021-10-19	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_4) - 70eV, Positive	Not Available	2021-10-19	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_5) - 70eV, Positive	Not Available	2021-10-19	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0bti-0110009330-a597d6786f2ec155d709	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0a4r-2311119000-a3fc63423a63d99a5fb7	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0udj-5692335100-c9dcfe66d206e059a42a	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0ik9-0912217680-c23ce8bf8a7dc6585c65	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0f6x-0913128500-dfbbb5029daf5212939d	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0ktf-7812694000-d210db4913a3e8fedd3d	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-03di-0100001190-101d9f97452eadd98caa	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-074i-2400009320-dd1ca952f0b45c335762	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-002f-2900002100-7a252e17a6b4beea42fb	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-03di-0110001390-4bf88a3178c537fe09a1	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-08gi-1900002750-173fb451507d24f93587	2021-10-11	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-06r2-3910001000-6b208b50ef647efcc9fc	2021-10-11	View Spectrum

Toxicity Profile

Route of Exposure

Absolute bioavailability is approximately 57%. Maximal concentrations are reached 0.5 - 4 hours following oral administration. Food intake does not affected absorption.

Mechanism of Toxicity

Telithromycin acts by binding to domains II and V of 23S rRNA of the 50S ribosomal subunit. By binding at domain II, telithromycin retains activity against gram-positive cocci (e.g., Streptococcus pneumoniae) in the presence of resistance mediated by methylases (erm genes) that alter the domain V binding site of telithromycin. Telithromycin may also inhibit the assembly of nascent ribosomal units. Compared to erythromycin A, telithromycin binds to the 23S rRNA with 10 times greater affinity in erythromycin-susceptible organisms and 25 times greater affinity in macrolide-resistant strains. This increased binding affinity may be conferred by the C11-12 carbamate side chain of telithromycin. The side chain appears to maintain binding at domain II in the presence of resistance mediated by alterations in domain V.

Metabolism

Hepatic - estimated 50% metabolized by CYP3A4 and 50% metabolized independent of cytochrome P450 Route of Elimination: The systemically available telithromycin is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in feces by biliary and/or intestinal secretion; 13% of the dose is excreted unchanged in urine by renal excretion; and 37% of the dose is metabolized by the liver. Half Life: Main elimination half-life is 2-3 hours; terminal elimination half-life is 10 hours

Toxicity Values

LD50>2000 mg/kg (PO in rats).

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

For the treatment of Pneumococcal infection, acute sinusitis, acute bacterial tonsillitis, acute bronchitis and bronchiolitis, lower respiratory tract infection and lobar (pneumococcal) pneumonia.

Minimum Risk Level

Not Available

Health Effects

Not Available

Symptoms

Most common side-effects are gastrointestinal, including diarrhea, nausea, abdominal pain and vomiting. Headache and disturbances in taste also occur. Less common side-effects include palpitations, blurred vision and rashes. [Wikipedia]

Treatment

Not Available

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

Not Available

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Telithromycin

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Telithromycin

References

Synthesis Reference

Suhas Sohani, Mandar Deodhar, Nishant Patel, Manish Patel, Mahesh Davadra, Vinodhamar Kansal, “Process for the Preparation of Telithromycin.” U.S. Patent US20070260066, issued November 08, 2007.

MSDS

Link

General References

Clay KD, Hanson JS, Pope SD, Rissmiller RW, Purdum PP 3rd, Banks PM: Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review. Ann Intern Med. 2006 Mar 21;144(6):415-20. Epub 2006 Feb 15. [16481451 ]
Drugs.com [Link]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. Cytochrome P450 3A4

General Function:: Vitamin d3 25-hydroxylase activity
Specific Function:: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599).
Gene Name:: CYP3A4
Uniprot ID:: P08684
Molecular Weight:: 57342.67 Da

References

Bearden DT, Neuhauser MM, Garey KW: Telithromycin: an oral ketolide for respiratory infections. Pharmacotherapy. 2001 Oct;21(10):1204-22. [11601667 ]
Zhanel GG, Walters M, Noreddin A, Vercaigne LM, Wierzbowski A, Embil JM, Gin AS, Douthwaite S, Hoban DJ: The ketolides: a critical review. Drugs. 2002;62(12):1771-804. [12149046 ]
Reed M, Wall GC, Shah NP, Heun JM, Hicklin GA: Verapamil toxicity resulting from a probable interaction with telithromycin. Ann Pharmacother. 2005 Feb;39(2):357-60. Epub 2004 Dec 14. [15598962 ]
Shi J, Chapel S, Montay G, Hardy P, Barrett JS, Sica D, Swan SK, Noveck R, Leroy B, Bhargava VO: Effect of ketoconazole on the pharmacokinetics and safety of telithromycin and clarithromycin in older subjects with renal impairment. Int J Clin Pharmacol Ther. 2005 Mar;43(3):123-33. [15792396 ]
Nguyen M, Chung EP: Telithromycin: the first ketolide antimicrobial. Clin Ther. 2005 Aug;27(8):1144-63. [16199242 ]

Target Details

2. Cytochrome P450 3A4

General Function:: Vitamin d3 25-hydroxylase activity
Specific Function:: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599).
Gene Name:: CYP3A4
Uniprot ID:: P08684
Molecular Weight:: 57342.67 Da

References

Bearden DT, Neuhauser MM, Garey KW: Telithromycin: an oral ketolide for respiratory infections. Pharmacotherapy. 2001 Oct;21(10):1204-22. [11601667 ]
Zhanel GG, Walters M, Noreddin A, Vercaigne LM, Wierzbowski A, Embil JM, Gin AS, Douthwaite S, Hoban DJ: The ketolides: a critical review. Drugs. 2002;62(12):1771-804. [12149046 ]
Reed M, Wall GC, Shah NP, Heun JM, Hicklin GA: Verapamil toxicity resulting from a probable interaction with telithromycin. Ann Pharmacother. 2005 Feb;39(2):357-60. Epub 2004 Dec 14. [15598962 ]
Shi J, Chapel S, Montay G, Hardy P, Barrett JS, Sica D, Swan SK, Noveck R, Leroy B, Bhargava VO: Effect of ketoconazole on the pharmacokinetics and safety of telithromycin and clarithromycin in older subjects with renal impairment. Int J Clin Pharmacol Ther. 2005 Mar;43(3):123-33. [15792396 ]
Nguyen M, Chung EP: Telithromycin: the first ketolide antimicrobial. Clin Ther. 2005 Aug;27(8):1144-63. [16199242 ]

Target Details

3. Cytochrome P450 2D6

General Function:: Steroid hydroxylase activity
Specific Function:: Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:: CYP2D6
Uniprot ID:: P10635
Molecular Weight:: 55768.94 Da

References

Nguyen M, Chung EP: Telithromycin: the first ketolide antimicrobial. Clin Ther. 2005 Aug;27(8):1144-63. [16199242 ]
Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [19934256 ]

Target Details

4. Cytochrome P450 1A2

General Function:: Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function:: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen. Participates in the bioactivation of carcinogenic aromatic and heterocyclic amines. Catalizes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin.
Gene Name:: CYP1A2
Uniprot ID:: P05177
Molecular Weight:: 58293.76 Da

References

Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [19934256 ]

Target Details

5. Cytochrome P450 3A5

General Function:: Oxygen binding
Specific Function:: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:: CYP3A5
Uniprot ID:: P20815
Molecular Weight:: 57108.065 Da

References

Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010 [Link]

Target Details

6. Cytochrome P450 3A7

General Function:: Oxygen binding
Specific Function:: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:: CYP3A7
Uniprot ID:: P24462
Molecular Weight:: 57525.03 Da

References

Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010 [Link]

Telithromycin (T3D3536)

Structure for T3D3536: Telithromycin

Targets

References

References

References

References

References

References