Tavaborole | C7H6BFO2 - PubChem
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`NIH
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`U.S. National Library of Medicine
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`National Center for Biotechnology Information
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`Search Compounds
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`
`
` Compound Summary for CID 11499245
`
`Tavaborole
`
` Cite this Record
`
`
`
`
`
`
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`
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`
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`
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`STRUCTURE
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`VENDORS
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`DRUG INFO
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`PHARMACOLOGY
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`LITERATURE
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`PATENTS
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`BIOACTIVITIES
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`PubChem CID:
`
`11499245
`
`Tavaborole; 174671-46-6; AN-2690; 5-FLUOROBENZO[C][1,2]OXABOROL-1(3H)-OL;
`
`Chemical Names:
`
`Kerydin; AN 2690   
`
`More...
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`Molecular Formula:
`
`Molecular Weight:
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`C H BFO
`7
`6
`2
`151.931 g/mol
`
`InChI Key:
`
`LFQDNHWZDQTITF-UHFFFAOYSA-N
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`Drug Indication
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`Therapeutic Uses
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`Clinical Trials
`
`FDA Orange Book
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`Drug Information:
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`FDA UNII
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`Safety Summary:
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`Laboratory Chemical Safety Summary (LCSS)
`
`Tavaborole is an Oxaborole Antifungal. The mechanism of action of tavaborole is as a Protein Synthesis Inhibitor.
`The chemical classification of tavaborole is Boron Compounds.
` FDA Pharmacology Summary from FDA Pharm Classes
`
`5-Fluoro-1 3-Dihydro-1-Hydroxy-2 1-Benzoxaborole is a boron-containing small molecule antifungal agent with
`broad-spectrum activity against filamentous fungi, including both mold and yeast. 5-Fluoro-1,3-dihydro-1-
`hydroxy-2,1-benzoxaborole inhibits fungal cytoplasmic leucyl-tRNA synthetase by preventing catalytic turnover,
`thus inhibiting synthesis of leucyl-tRNA(Leu) and consequentially blocking protein synthesis.
` Pharmacology from NCIt
`
`PUBCHEM
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`
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`COMPOUND
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`
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`TAVABOROLE
`
`Create Date: 2006-10-26
`
`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
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` Contents
`1 2D Structure
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`2 3D Status
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`3 Names and Identifiers
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`4 Chemical and Physical Properties
`
`5 Related Records
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`6 Chemical Vendors
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`7 Drug and Medication Information
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`8 Pharmacology and Biochemistry
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`9 Use and Manufacturing
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`10 Safety and Hazards
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`11 Toxicity
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`12 Literature
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`13 Patents
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`14 Biomolecular Interactions and Pathways
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`15 Biological Test Results
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`16 Classification
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`17 Information Sources
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`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
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`1 2D Structure
`
` Search
`
` Download
`
` Get Image
`
` Magnify
`
` from PubChem
`
`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
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`2 3D Status
`
`Conformer generation is disallowed since MMFF94s unsupported element
`
` from PubChem
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`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
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`3 Names and Identifiers
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`3.1 Computed Descriptors
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`3.1.1 IUPAC Name
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`5-fluoro-1-hydroxy-3H-2,1-benzoxaborole
`
`3.1.2 InChI
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`InChI=1S/C7H6BFO2/c9-6-1-2-7-5(3-6)4-11-8(7)10/h1-3,10H,4H2
`
`3.1.3 InChI Key
`
`LFQDNHWZDQTITF-UHFFFAOYSA-N
`
`3.1.4 Canonical SMILES
`
`B1(C2=C(CO1)C=C(C=C2)F)O
`
`3.2 Molecular Formula
`
`C H BFO
`7
`6
`2
`
`3.3 Other Identifiers
`
`3.3.1 CAS
`
`174671-46-6
`
` from PubChem
`
` from PubChem
`
` from PubChem
`
` from PubChem
`
` from PubChem
`
` from ChemIDplus, DrugBank
`
`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
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`3.3.2 UNII
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`K124A4EUQ3
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`3.3.3 Wikipedia
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`Title
`
`Description
`
`tavaborole
`
`chemical compound
`
`3.4 Synonyms
`
`3.4.1 MeSH Synonyms
`
`1. 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
`2. AN 2690
`3. AN-2690
`4. AN2690
`5. Kerydin
`6. tavaborole
`
`3.4.2 Depositor-Supplied Synonyms
`
`1. Tavaborole
`2. 174671-46-6
`3. AN-2690
`4. 5-FLUOROBENZO[C][1,2]OXABOROL-1(3H)-OL
`5. Kerydin
`6. AN 2690
`7. UNII-K124A4EUQ3
`8. AN2690
`9. 2,1-Benzoxaborole, 5-fluoro-1,3-dihydro-1-hydroxy-
`10. K124A4EUQ3
`
`
` from FDA/SPL Indexing Data
`
` from Wikipedia
`
` from MeSH
`
`11. CHEBI:77942
`12. 5-fluoro-1,3-dihydro-2,1-benzoxaborol-1-ol
`13. 5-Fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole
`14. 5-fluoro-2,1-benzoxaborol-1(3H)-ol
`15. AK163946
`16. C7H6BFO2
`17. 5-Fluoro-3H-benzo[c][1,2)oxaborol-1-ol
`18. 5-fluoro-3H-benzo[c][1,2]oxaborol-1-ol
`19. Tavaborole [USAN:INN]
`20. Kerydin (TN)
`
`
` from PubChem
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`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
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`4 Chemical and Physical Properties
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`4.1 Computed Properties
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`Property Name
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`Molecular Weight
`
`Hydrogen Bond Donor Count
`
`Hydrogen Bond Acceptor Count
`
`Rotatable Bond Count
`
`Complexity
`
`CACTVS Substructure Key Fingerprint
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`Topological Polar Surface Area
`
`Monoisotopic Mass
`
`Exact Mass
`
`Compound Is Canonicalized
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`Formal Charge
`
`Heavy Atom Count
`
`Defined Atom Stereocenter Count
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`Undefined Atom Stereocenter Count
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`Defined Bond Stereocenter Count
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`Undefined Bond Stereocenter Count
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`Isotope Atom Count
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`Covalently-Bonded Unit Count
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`4.2 Experimental Properties
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`4.2.1 Color
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`Property Value
`
`151.931 g/mol
`
`1
`
`3
`
`0
`
`155
`
`AAADcYJgMQAAAAAAAAAAAAAAAAAAASAAAAAw
`AAAAAAAAAEgBAAAoGwAACAAADACgmAowAIAA
`AACAAiBCAAACAAAgAAAIiAAACIgIJiKAERCAMAAk
`wAEIiAeAwCAOAAAAAAAAAAAAAAAAAAAAAAAAA
`AAA
`
`29.5 A^2
`
`152.044 g/mol
`
`152.044 g/mol
`
`true
`
`0
`
`11
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1
`
` from PubChem
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`White to off-white powder
`NIH; DailyMed. Current Medication Information for Kerydin (Tavaborole) Solution (Updated: January 2015). Available from,
`as of July 5, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6ba6f49-0055-4285-9e04-67001d4554fd
` from HSDB
`
`4.2.2 Solubility
`
`In water, 6029 mg/L at 25 deg C (est)
`US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available from, as of Jun 23, 2016:
`http://www2.epa.gov/tsca-screening-tools
`
` from HSDB
`
`Slightly soluble in water
`NIH; DailyMed. Current Medication Information for Kerydin (Tavaborole) Solution (Updated: January 2015). Available from,
`as of July 5, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6ba6f49-0055-4285-9e04-67001d4554fd
` from HSDB
`
`Freely soluble in ethanol, propylene glycol
`NIH; DailyMed. Current Medication Information for Kerydin (Tavaborole) Solution (Updated: January 2015). Available from,
`as of July 5, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6ba6f49-0055-4285-9e04-67001d4554fd
` from HSDB
`
`4.2.3 Vapor Pressure
`
`3.25X10-3 mm Hg at 25 deg C (est)
`US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available from, as of Jun 23, 2016:
`http://www2.epa.gov/tsca-screening-tools
`
` from HSDB
`
` from HSDB
`
` 
`
`4.2.4 LogP
`
`log Kow = 1.28 (est)
`US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available from, as of Jun 23, 2016:
`http://www2.epa.gov/tsca-screening-tools
`
`4.3 Crystal Structures
`
`Crystal Structures: 1 of 2
`
`CCDC Number
`
`986106
`
`Crystal Structure Data
`
`DOI:10.5517/cc1233w5
`
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`Crystal Structures: 1 of 2
`
`Associated Article
`
`DOI:10.1039/C4CE00313F
`
` from The Cambridge Structural Database
`
`Crystal Structures: 2 of 2
`
`CCDC Number
`
`811360
`
`Crystal Structure Data
`
`DOI:10.5517/ccw78x8
`
`Associated Article
`
`DOI:10.1107/S1600536811001632
`
` from The Cambridge Structural Database
`
`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
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`5 Related Records
`
`CLICK TO LOAD...
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`5.1 Related Compounds with Annotation
`
`CLICK TO LOAD...
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`5.2 Related Compounds
`
`Same Connectivity
`
`Same Parent, Connectivity
`
`Same Parent, Exact
`
`Mixtures, Components, and
`Neutralized Forms
`
`3 records
`
`4 records
`
`2 records
`
`4 records
`
`Similar Compounds
`
`88 records
`
` from NCBI
`
` from PubChem
`
` from PubChem
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`5.3 Substances
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`5.3.1 Related Substances
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`All
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`Same
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`Mixture
`
`68 records
`
`64 records
`
`4 records
`
`5.3.2 Substances by Category
`
`CLICK TO LOAD...
`
`5.4 Entrez Crosslinks
`
`PubMed
`
`15 records
`
` from PubChem
`
` from PubChem
`
` from PubChem
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`6 Chemical Vendors
`
`CLICK TO LOAD...
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` from PubChem
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`7 Drug and Medication Information
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`7.1 Drug Indication
`
`Indicated for the treatment of onychomycosis (a fungal infection) of the toenails due to Trichophyton rubrum
`or Trichophyton mentagrophytes.
`
`For the treatment of onychomycosis, a fungal infection of the nail and nail bed.
`
` from DrugBank
`
` from DrugBank
`
`7.2 FDA Orange Book
`
`7.2.1 Prescription Drug Products
`
`Drug Ingredient
`
`Proprietary Name
`
`Applicant
`
`TAVABOROLE
`
`KERYDIN
`
`ANACOR PHARMS INC (Application Number: N204427. Patents: 7582621,
`7767657, 9549938, 9566289, 9566290, 9572823)
`
` from FDA Orange Book
`
`7.3 Drug Labels for Ingredients
`
`Label Title
`
`Drug Ingredient
`
`Label Image
`
`KERYDIN- tavaborole solution
`
`TAVABOROLE
`
`CLICK TO LOAD...
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`Label Download
`
`PDF Label
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`NDC Code(s)
`
`NDC Code(s)
`10337-905-10, 10337-905-44
`
`Packager
`
`PharmaDerm, A division of Fougera Pharmaceuticals Inc.
`
`7.4 Drugs at PubMed Health
`
`Drugs at PubMed Health: 1 of 2
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`Drug Name
`
`Notes
`
`Kerydin
`
`See Tavaborole (Topical application route)
`
`Drugs at PubMed Health: 2 of 2
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`Drug Name
`
`Description
`
`Drug Classes
`
`Tavaborole (Topical application route)
`
`Treats fungal infection of the toenails.
`
`Antifungal
`
` from DailyMed
`
` from PubMed Health
`
` from PubMed Health
`
`7.5 Clinical Trials
`
`1 to 5 of 5
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`Record ID
`
`Title
`
`NCT00680160
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`Absorption and Systemic Study of AN2690 in Patients With
`Moderate to Severe Onychomycosis (ADME I)
`
`NCT00680134
`
`Safety and Efficacy Evaluation of Topically Applied AN2690 Solutions
`for Subjects With Onychomycosis
`
`NCT00680095 Cumulative Irritation Test
`
` Download
`
`Status
`
`Phase
`
`Completed 2
`
`Completed 2
`
`Completed 1
`
`NCT00679965 Study of Different Doses of a Novel Treatment for Onychomycosis
`
`Completed 2
`
`NCT00679601
`
`Completed 2
`
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`Record ID
`
`Title
`Absorption and Systemic Study of AN2690 in Patients With
`Moderate to Severe Onychomycosis (ADME II)
`
`Status
`
`Phase
`
` from ClinicalTrials.gov
`
`7.6 Therapeutic Uses
`
`Antifungal Agents
`National Library of Medicine's Medical Subject Headings. Tavaborole. Online file (MeSH, 2016). Available from, as of June
`24, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html
`
` from HSDB
`
`/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported
`clinical studies of human participants conducted around the world. The Web site is maintained by the National
`Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents
`summary information about a study protocol and includes the following: Disease or condition; Intervention
`(for example, the medical product, behavior, or procedure being studied); Title, description, and design of the
`study; Requirements for participation (eligibility criteria); Locations where the study is being conducted;
`Contact information for the study locations; and Links to relevant information on other health Web sites, such
`as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly
`articles in the field of medicine. Tavaborole is included in the database.
`NIH/NLM; ClinicalTrials.Gov. Available from, as of July 6, 2016:
`https://clinicaltrials.gov/search/intervention=AN2690+OR+AN+2690%20OR%20Tavaborole
`
` from HSDB
`
`Kerydin (tavaborole) topical solution, 5% is an oxaborole antifungal indicated for the treatment of
`onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes. /Included in US
`product label/
`NIH; DailyMed. Current Medication Information for Kerydin (Tavaborole) Solution (Updated: January 2015). Available from,
`as of July 5, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6ba6f49-0055-4285-9e04-67001d4554fd
` from HSDB
`
`7.7 Drug Warning
`
`Adverse effects reported in at least 1% of adults treated with tavaborole 5% topical solution and more
`frequently than with topical vehicle solution include application site exfoliation, ingrown toenail, application
`site erythema, and application site dermatitis.
`American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016
`
` from HSDB
`
`Tavaborole 5% topical solution may cause skin irritation; there is no evidence to date that the solution causes
`contact sensitization.
`American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016
`
`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
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` from HSDB
`
`It is not known whether tavaborole is excreted in human milk following topical application of Kerydin. Because
`many drugs are excreted in human milk, caution should be exercised when Kerydin is administered to a
`nursing woman.
`NIH; DailyMed. Current Medication Information for Kerydin (Tavaborole) Solution (Updated: January 2015). Available from,
`as of July 5, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6ba6f49-0055-4285-9e04-67001d4554fd
` from HSDB
`
`There are no adequate and well-controlled studies with Kerydin in pregnant women. Kerydin should be used
`during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`NIH; DailyMed. Current Medication Information for Kerydin (Tavaborole) Solution (Updated: January 2015). Available from,
`as of July 5, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6ba6f49-0055-4285-9e04-67001d4554fd
` from HSDB
`
`In clinical trials of 791 subjects who were exposed to Kerydin, 19% were 65 years of age and over, while 4%
`were 75 years of age and over. No overall differences in safety or effectiveness were observed between these
`subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
`NIH; DailyMed. Current Medication Information for Kerydin (Tavaborole) Solution (Updated: January 2015). Available from,
`as of July 5, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6ba6f49-0055-4285-9e04-67001d4554fd
` from HSDB
`
`Safety and effectiveness in pediatric patients have not been established.
`NIH; DailyMed. Current Medication Information for Kerydin (Tavaborole) Solution (Updated: January 2015). Available from,
`as of July 5, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6ba6f49-0055-4285-9e04-67001d4554fd
` from HSDB
`
`FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are
`lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if
`the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
`NIH; DailyMed. Current Medication Information for Kerydin (Tavaborole) Solution (Updated: January 2015). Available from,
`as of July 5, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6ba6f49-0055-4285-9e04-67001d4554fd
` from HSDB
`
`Tavaborole 5% solution is for topical use only. The topical solution should not be used orally or intravaginally,
`and should not be applied to the eyes.
`American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016
`
` from HSDB
`
`Prior to treatment of onychomycosis, the diagnosis should be confirmed by direct microscopic examination of
`scrapings from infected toenails mounted in potassium hydroxide (KOH) or by culture.
`American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016
`
` from HSDB
`
`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
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`8 Pharmacology and Biochemistry
`
`8.1 Pharmacology
`
`After a single dose, the mean (± standard deviation) peak concentration (Cmax) of tavaborole was 3.54 ± 2.26
`ng/mL (n=21 with measurable concentrations, range 0.618-10.2 ng/mL, LLOQ=0.5 ng/mL), and the mean
`AUClast was 44.4 ± 25.5 ng*hr/mL (n=21). After 2 weeks of daily dosing, the mean Cmax was 5.17 ± 3.47
`ng/mL (n=24, range 1.51-12.8 ng/mL), and the mean AUC? was 75.8 ± 44.5 ng*hr/mL.
`
` from DrugBank
`
`5-Fluoro-1 3-Dihydro-1-Hydroxy-2 1-Benzoxaborole is a boron-containing small molecule antifungal agent
`with broad-spectrum activity against filamentous fungi, including both mold and yeast. 5-Fluoro-1,3-dihydro-
`1-hydroxy-2,1-benzoxaborole inhibits fungal cytoplasmic leucyl-tRNA synthetase by preventing catalytic
`turnover, thus inhibiting synthesis of leucyl-tRNA(Leu) and consequentially blocking protein synthesis.
` from NCIt
`
`8.2 MeSH Pharmacological Classification
`
`Antifungal Agents
`Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES,
`INDUSTRIAL because they defend against fungi present in human or animal tissues. See a list of PubChem
`compounds matching this category.
`
` from MeSH
`
`8.3 FDA Pharmacological Classification
`
`8.3.1 Active Moiety
`
`TAVABOROLE
`
`8.3.2 FDA UNII
`
`K124A4EUQ3
`
`8.3.3 Pharmacological Classes
`
`Oxaborole Antifungal
`
` from FDA Pharm Classes
`
` from FDA Pharm Classes
`
`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
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`Page 20 of 43
`
`Established Pharmacologic
`Class [EPC]
`
`Mechanisms of Action [MoA]
`
`Protein Synthesis Inhibitors
`
`Chemical/Ingredient structural
`concept [Chemical/Ingredient]
`
`Boron Compounds
`
` from FDA Pharm Classes
`
`8.4 Absorption, Distribution and Excretion
`
`Subungual onychomycosis is difficult to treat due to the poorly perfused location of the infection in the
`nailbed. To be effective, a topical treatment must penetrate the nail plate and reach the site of infection at a
`concentration sufficient to exert anti-fungal activity. Tavaborole was shown to produce anti-fungal effects after
`5 days of topical administration.
`
`Route of Elimination
`Primarily renal.
`
`7.5%
`
` from DrugBank
`
` from DrugBank
`
` from DrugBank
`
`The pharmacokinetics of tavaborole was investigated in 24 subjects with distal subungual onychomycosis
`involving at least 4 toenails (including at least 1 great toenail) following a single dose and a 2-week daily
`topical application of 200 uL of a 5% solution of tavaborole to all ten toenails and 2 mm of skin surrounding
`each toenail. Steady state was achieved after 14 days of dosing. After a single dose, the mean (+ or - standard
`deviation) peak concentration (Cmax) of tavaborole was 3.54 + or - 2.26 ng/mL (n=21 with measurable
`concentrations, range 0.618-10.2 ng/mL, LLOQ=0.5 ng/mL), and the mean AUClast was 44.4 + or - 25.5
`ng*hr/mL (n=21). After 2 weeks of daily dosing, the mean Cmax was 5.17 + or - 3.47 ng/mL (n=24, range 1.51-
`12.8 ng/mL), and the mean AUCt was 75.8 + or - 44.5 ng*hr/mL.
`NIH; DailyMed. Current Medication Information for Kerydin (Tavaborole) Solution (Updated: January 2015). Available from,
`as of July 5, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6ba6f49-0055-4285-9e04-67001d4554fd
` from HSDB
`
`Renal excretion is the major route of elimination. In a clinical pharmacology trial of six healthy adult male
`volunteers who received a single topical application of 5% (14)C-tavaborole solution, tavaborole conjugates
`and metabolites were shown to be excreted primarily in the urine.
`NIH; DailyMed. Current Medication Information for Kerydin (Tavaborole) Solution (Updated: January 2015). Available from,
`as of July 5, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6ba6f49-0055-4285-9e04-67001d4554fd
` from HSDB
`
`/MILK/ It is not known whether tavaborole is excreted in human milk following topical application of Kerydin.
`NIH; DailyMed. Current Medication Information for Kerydin (Tavaborole) Solution (Updated: January 2015). Available from,
`as of July 5, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6ba6f49-0055-4285-9e04-67001d4554fd
`
`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
`
`5/26/2017
`
`FlatWing Ex. 1027, p. 20
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`

`

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`Page 21 of 43
`
` from HSDB
`
`Onychomycosis is a common infection of the toenails that causes nail thickening and discoloration. The
`physical appearance of the infected nail can diminish self-image and negatively impact quality of life. Patients
`may use nail polish to mask the appearance of infected nails. /The purpose of this study was/ to evaluate the
`in vitro nail penetration properties of tavaborole topical solution, 5%, through nail polish using ex vivo, non-
`diseased human fingernails. In study 1, tavaborole penetration was evaluated over 20 days of dosing using the
`Franz finite dose technique and modified Franz diffusion cells. Nails received either 1 coat of over-the-counter
`(OTC) typical polish or were left unpolished (controls). In study 2, tavaborole penetration was measured over
`14 days of dosing using the finite dose technique and vertical diffusion cells. Nails were polished with either 4
`coats or 1 coat of salon typical polish or with 2 coats or 1 coat of OTC typical polish, or they were left
`unpolished. In study 1, the mean + or - standard deviation (SD) cumulative tavaborole penetration at day 21
`was numerically higher, though not statistically significant, through polished nails (3,526 + or - 1,433 ug/sq
`cm)vs unpolished nails (2,661 + or - 1,319 ug/sq cm).In study 2, the mean cumulative tavaborole penetration
`was also numerically higher (statistical significance not assessed) through all nails that received polish vs
`unpolished nails. At day 15, mean + or - SD cumulative tavaborole nail penetration was 1,179 + or - 554 ug/sq
`cm through 4 coats of salon typical polish, 1,227 + or - 974 ug/sq cm through 1 coat of salon typical polish,
`1,493 + or - 1,322 ug/sq cm through 2 coats of OTC typical polish, 1,428 + or - 841 ug/sq cm through 1 coat
`of OTC typical polish, and 566 + or - 318 ug/sq cm through unpolished nails. Results from these in vitro
`studies demonstrated that tavaborole penetrated through human nails with up to 4 layers of nail polish.
`Abstract: PubMed
`Vlahovic T et al; J Drugs Dermatol 14 (7): 675-8 (2015)
`
` from HSDB
`
`8.5 Metabolism/Metabolites
`
`Tavaborole undergoes extensive metabolism. Metabolite profiling revealed trace levels of a sulfated-conjugate
`and a benzoic acid metabolite, consistent with the known biotransformation of tavaborole.
`
` from DrugBank
`
`Tavaborole undergoes extensive metabolism. ... In a clinical pharmacology trial of six healthy adult male
`volunteers who received a single topical application of 5% (14)C-tavaborole solution, tavaborole conjugates
`and metabolites were shown to be excreted primarily in the urine.
`NIH; DailyMed. Current Medication Information for Kerydin (Tavaborole) Solution (Updated: January 2015). Available from,
`as of July 5, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6ba6f49-0055-4285-9e04-67001d4554fd
` from HSDB
`
`8.6 Biological Half-Life
`
`28.5 hr
`
`8.7 Mechanism of Action
`
` from DrugBank
`
`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
`
`5/26/2017
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`FlatWing Ex. 1027, p. 21
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`
`Tavaborole exerts its antifungal activity by blocking cellular protein synthesis through the formation of an
`adduct with cytoplasmic leucyl-aminoacyl transfer RNA (tRNA) synthetase.
`
` from DrugBank
`
`AN2690 has a novel mechanism of action that targets an essential protein synthesis enzyme, leucyl-transfer
`RNA synthetase, or LeuRS. This enzyme plays a pivotal role in fungal protein synthesis. The inhibition of
`protein synthesis leads to termination of cell growth or cell death, eliminating the fungal infection.
` from DrugBank
`
`The broad-spectrum benzoxaborole antifungal AN2690 /tavaborole/ blocks protein synthesis by inhibiting
`leucyl-tRNA synthetase (LeuRS) via a novel oxaborole tRNA trapping mechanism in the editing site. Herein,
`one set of resistance mutations is at Asp487 outside the LeuRS hydrolytic editing pocket, in a region of
`unknown function. It is located within a eukaryote/archaea specific insert I4, which forms part of a cap over a
`benzoxaborole-AMP that is bound in the LeuRS CP1 domain editing active site. Mutational and biochemical
`analysis at Asp487 identified a salt bridge between Asp487 and Arg316 in the hinge region of the I4 cap of
`yeast LeuRS that is critical for tRNA deacylation. We hypothesize that this electrostatic interaction stabilizes the
`cap during binding of the editing substrate for hydrolysis.[Sarkar J et al; FEBS Lett 585 (19): 2986-91 (2011)]
`Full text: PMC3225056 Abstract: PubMed
`
` from HSDB
`
`The mechanism of action of tavaborole against susceptible fungi involves inhibition of fungal protein synthesis
`by inhibition of an aminoacyl-transfer ribonucleic acid (tRNA) synthetase (AARS). Tavaborole inhibits the
`editing domain of leucyl-tRNA synthetase and exhibits good relative selectivity for this fungal enzyme.
`American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016
`
` from HSDB
`
`Leucyl-tRNA synthetase (LeuRS) specifically links leucine to the 3' end of tRNA(leu) isoacceptors. The overall
`accuracy of the two-step aminoacylation reaction is enhanced by an editing domain that hydrolyzes
`mischarged tRNAs, notably ile-tRNA(leu). We present crystal structures of the editing domain from two
`eukaryotic cytosolic LeuRS: human and fungal pathogen Candida albicans. In comparison with previous
`structures of the editing domain from bacterial and archeal kingdoms, these structures show that the LeuRS
`editing domain has a conserved structural core containing the active site for hydrolysis, with distinct bacterial,
`archeal, or eukaryotic specific peripheral insertions. It was recently shown that the benzoxaborole antifungal
`compound AN2690 (5-fluoro-1,3-dihydro-1-hydroxy-1,2-benzoxaborole) inhibits LeuRS by forming a covalent
`adduct with the 3' adenosine of tRNA(leu) at the editing site, thus locking the enzyme in an inactive
`conformation. To provide a structural basis for enhancing the specificity of these benzoxaborole antifungals,
`we determined the structure at 2.2 A resolution of the C. albicans editing domain in complex with a related
`compound, AN3018 (6-(ethylamino)-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol), using AMP as a surrogate for
`the 3' adenosine of tRNA(leu). The interactions between the AN3018-AMP adduct and C. albicans LeuRS are
`similar to those previously observed for bacterial LeuRS with the AN2690 adduct, with an additional hydrogen
`bond to the extra ethylamine group. However, compared to bacteria, eukaryotic cytosolic LeuRS editing
`domains contain an extra helix that closes over the active site, largely burying the adduct and providing
`additional direct and water-mediated contacts. Small differences between the human domain and the fungal
`domain could be exploited to enhance fungal specificity. Abstract: PubMed
`Seiradake E et al; J Mol Biol 390 (2): 196-207 (2009)
`
` from HSDB
`
`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
`
`5/26/2017
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`FlatWing Ex. 1027, p. 22
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`Page 23 of 43
`
`Aminoacyl-transfer RNA (tRNA) synthetases, which catalyze the attachment of the correct amino acid to its
`corresponding tRNA during translation of the genetic code, are proven antimicrobial drug targets. We show
`that the broad-spectrum antifungal 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), in
`development for the treatment of onychomycosis, inhibits yeast cytoplasmic leucyl-tRNA synthetase by
`formation of a stable tRNA(Leu)-AN2690 adduct in the editing site of the enzyme. Adduct formation is
`mediated through the boron atom of AN2690 and the 2'- and 3'-oxygen atoms of tRNA's3'-terminal
`adenosine. The trapping of enzyme-bound tRNA(Leu) in the editing site prevents catalytic turnover, thus
`inhibiting synthesis of leucyl-tRNA(Leu) and consequentially blocking protein synthesis. This result establishes
`the editing site as a bona fide target for aminoacyl-tRNA synthetase inhibitors. Abstract: PubMed
`Rock FL et al; Science 316 (5832): 1759-61 (2007)
`
` from HSDB
`
`A new class of antimicrobial benzoxaborole compounds was identified as a potent inhibitor of leucyl-tRNA
`synthetase (LeuRS) and therefore of protein synthesis. In a novel mechanism, AN2690 (5-fluoro-1,3-dihydro-1-
`hydroxy-2,1-benzoxaborole) blocks fungal cytoplasmic LeuRS by covalently trapping tRNA(Leu) in the editing
`site of the enzyme's CP1 domain. However, some resistant mutation sites are located outside of the CP1
`hydrolytic editing active site. Thus, their mode of action that undermines drug inhibition was not understood.
`A combination of X-ray crystallography, molecular dynamics, metadynamics, biochemical experiments, and
`mutational analysis of a distal benzoxaborole-resistant mutant uncovered a eukaryote-specific tyrosine
`"switch" that is critical to tRNA-dependent post-transfer editing. The tyrosine "switch" has three states that
`shift between interactions with a lysine and the 3'-hydroxyl of the tRNA terminus, to inhibit or promote post-
`transfer editing. The oxaborole's mechanism of action capitalizes upon one of these editing active site states.
`This tunable editing mechanism in eukaryotic and archaeal LeuRSs is proposed to facilitate precise quality
`control of aminoacylation fidelity. These mechanistic distinctions could also be capitalized upon for
`development of the benzoxaboroles as a broad spectrum antibacterial. Abstract: PubMed
`Zhao H et al; ACS Chem Biol 10 (10): 2277-85 (2015)
`
` from HSDB
`
`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
`
`5/26/2017
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`FlatWing Ex. 1027, p. 23
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`Page 24 of 43
`
`9 Use and Manufacturing
`
`9.1 Formulations/Preparations
`
`For the topical treatment of onychomycosis, tavaborole is commercially available as a 5% solution. Each mL of
`the clear, colorless solution contains 43.5 mg of tavaborole in an alcohol-based vehicle. The topical solution
`also contains edetate calcium disodium and propylene glycol.
`American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016
`
`Topical: Solution, 5%, (Kerydin), Anacor.
`American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016
`
` from HSDB
`
` from HSDB
`
`https://pubchem.ncbi.nlm.nih.gov/compound/11499245
`
`5/26/2017
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`FlatWing Ex. 1027, p. 24
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`
`10 Safety and Hazards
`
`10.1 Hazards Identification
`
`10.1.1 GHS Classification
`
`Signal: Danger
`GHS Hazard Statements
`Aggregated GHS information from 3 notifications provided by 48 companies to the ECHA C&L Inventory. Each
`notification may be associated with multiple companies.
`
`H302 (95.83%): Harmful if swallowed [Warning Acute toxicity, oral - Category 4]
`H312 (95.83%): Harmful in contact with skin [Warning Acute toxicity, dermal - Category 4]
`H315 (97.92%): Causes skin irritation [Warning Skin corrosion/irritation - Category 2]
`H318 (97.92%): Causes serious eye damage [Danger Serious eye damage/eye irritation - Category 1]
`H332 (95.83%): Harmful if inhaled [Warning Acute toxicity, inhalation - Category 4]
`
`Information may vary between notifications depending on impurities, additives, and other factors. The
`percentage value in parenthesis indicates the notified classification ratio from all companies. Only Hazard
`Codes with percentage values above 10% are shown.
`
`Precautionary Statement Codes
`P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P305+P351+P338, P310,
`P312, P321, P322, P330, P332+P313, P362, P363, and P501
`(The corresponding statement to each P-code can be found here.)
`
` from European Chemicals Agency - ECHA
`
`10.1.2 Fire Potential
`
`Tavaborole 5% solution is flammable and should not be stored or used near heat or open