Crisaborole

Identification

Summary

Crisaborole is a non-steroidal topical medication used for the treatment of mild-moderate atopic dermatitis.

Brand Names
Eucrisa
Generic Name
Crisaborole
DrugBank Accession Number
DB05219
Background

Crisaborole is a novel oxaborole approved by FDA on December 14, 2016 as Eucrisa, a topical treatment of for mild to moderate atopic dermatitis. This non-steroidal agent is efficacious in improving disease severity, reducing the risk of infection and reducing the signs and symptoms in patients 2 years old and older. It reduces the local inflammation in the skin and prevents further exacerbation of the disease with a good safety profile. Its structure contains a boron atom, which facilitates skin penetration and binding to the bimetal center of the phosphodiesterase 4 enzyme. It is currently under development as topical treatment of psoriasis.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 251.05
Monoisotopic: 251.075373
Chemical Formula
C14H10BNO3
Synonyms
  • Crisaborole
External IDs
  • AN-2728
  • AN2728

Pharmacology

Indication

Intended for the topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Crisaborole has broad-spectrum anti-inflammatory activity by mainly targeting phosphodiesterase 4 (PDE4) enzyme that is a key regulator of inflammatory cytokine production. As this enzyme is expressed in keratinocytes and immune cells, crisaborole mediates an anti-inflammatory effect on almost all inflammatory cells. Topical application of this drug is useful as it potentiates the localization of this drug in the skin and this anti-inflammatory activity is in the low micromolar range.

Mechanism of action

Inhibition of PDE4 by crisaborole leads to elevated levels of cyclic adenosine monophosphate (cAMP). Increased intracellular levels of cAMP inhibit the NF-kB pathway and suppress the release of pro-inflammatory mediators such as TNF-alfa and various interleukins that play a causative role in psoriasis and atopic dermatitis. Suppression of downstream effects in different cell types may explain the therapeutic role of crisaborole in immune-mediated skin diseases.

TargetActionsOrganism
UcAMP-specific 3',5'-cyclic phosphodiesterase 4A
inhibitor
Humans
UcAMP-specific 3',5'-cyclic phosphodiesterase 4B
inhibitor
Humans
UcAMP-specific 3',5'-cyclic phosphodiesterase 4C
inhibitor
Humans
UcAMP-specific 3',5'-cyclic phosphodiesterase 4D
inhibitor
Humans
Absorption

Systemic concentrations of crisaborole were reached by 8 days of twice-daily topical administration. It has low systemic absorption thus poses less risk for developing systemic side effects.

Volume of distribution

Not Available

Protein binding

Based on an in vitro study, crisaborole is 97% bound to human plasma proteins

Metabolism

Crisaborole is substantially metabolized into inactive metabolites. The major metabolite 5-(4-cyanophenoxy)-2-hydroxyl benzylalcohol (metabolite 1), is formed via hydrolysis; this metabolite is further metabolized into downstream metabolites, among which 5-(4-cyanophenoxy)-2-hydroxyl benzoic acid (metabolite 2), formed via oxidation, is also a major metabolite.

Route of elimination

Renal excretion of metabolites is the major route of elimination.

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Hypersensitivity reactions such as contact urticaria may occur and discontinuation of the treatment is advised. No evidence of mutagenic or clastrogenic potential as well as altered effects on fertility. Oral LD50 value for rats is >500mg/kg.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EucrisaOintment2 % w/wTopicalPfizer Canada Ulc2018-08-29Not applicableCanada flag
EucrisaOintment20 mg/1gTopicalPfizer Laboratories Div Pfizer Inc2017-01-30Not applicableUS flag
StaquisOintment20 mg/gCutaneousPfizer Europe Ma Eeig2020-12-16Not applicableEU flag
StaquisOintment20 mg/gCutaneousPfizer Europe Ma Eeig2020-12-16Not applicableEU flag
StaquisOintment20 mg/gCutaneousPfizer Europe Ma Eeig2020-12-16Not applicableEU flag
StaquisOintment20 mg/gCutaneousPfizer Europe Ma Eeig2020-12-16Not applicableEU flag
StaquisOintment20 mg/1gTopicalPharmacia & Upjohn Company LLC2020-11-01Not applicableUS flag

Categories

ATC Codes
D11AH06 — Crisaborole
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Ethers
Direct Parent
Diarylethers
Alternative Parents
Phenoxy compounds / Phenol ethers / Benzonitriles / Oxaborole derivatives / Boronic acid esters / Oxacyclic compounds / Organic metalloid salts / Nitriles / Organometalloid compounds / Hydrocarbon derivatives
Substituents
1,2-oxaborole derivative / Aromatic heteropolycyclic compound / Benzenoid / Benzonitrile / Boronic acid derivative / Boronic acid ester / Carbonitrile / Cyanide / Diaryl ether / Hydrocarbon derivative
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
Q2R47HGR7P
CAS number
906673-24-3
InChI Key
USZAGAREISWJDP-UHFFFAOYSA-N
InChI
InChI=1S/C14H10BNO3/c16-8-10-1-3-12(4-2-10)19-13-5-6-14-11(7-13)9-18-15(14)17/h1-7,17H,9H2
IUPAC Name
4-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile
SMILES
OB1OCC2=C1C=CC(OC1=CC=C(C=C1)C#N)=C2

References

General References
  1. Paller AS, Tom WL, Lebwohl MG, Blumenthal RL, Boguniewicz M, Call RS, Eichenfield LF, Forsha DW, Rees WC, Simpson EL, Spellman MC, Stein Gold LF, Zaenglein AL, Hughes MH, Zane LT, Hebert AA: Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016 Sep;75(3):494-503.e4. doi: 10.1016/j.jaad.2016.05.046. Epub 2016 Jul 11. [Article]
  2. Paton DM: Crisaborole: Phosphodiesterase inhibitor for treatment of atopic dermatitis. Drugs Today (Barc). 2017 Apr;53(4):239-245. doi: 10.1358/dot.2017.53.4.2604174. [Article]
  3. Zane LT, Hughes MH, Shakib S: Tolerability of Crisaborole Ointment for Application on Sensitive Skin Areas: A Randomized, Double-Blind, Vehicle-Controlled Study in Healthy Volunteers. Am J Clin Dermatol. 2016 Oct;17(5):519-526. [Article]
  4. Moustafa F, Feldman SR: A review of phosphodiesterase-inhibition and the potential role for phosphodiesterase 4-inhibitors in clinical dermatology. Dermatol Online J. 2014 May 16;20(5):22608. [Article]
KEGG Drug
D10873
PubChem Compound
44591583
PubChem Substance
175426957
ChemSpider
24701949
BindingDB
50277665
RxNav
1865953
ChEBI
134677
ChEMBL
CHEMBL484785
ZINC
ZINC000169748244
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Crisaborole
AHFS Codes
  • 84:06.00 — Anti-inflammatory Agents
FDA label
Download (185 KB)
MSDS
Download (42.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentAtopic Dermatitis (AD)1
4CompletedTreatmentAtopic Dermatitis (AD)1
4Not Yet RecruitingOtherAtopic Dermatitis (AD) / Dermatitis, Eczematous1
4RecruitingTreatmentAtopic Dermatitis (AD)1
4RecruitingTreatmentAtopic Dermatitis (AD) / Dermatitis, Eczematous1
4RecruitingTreatmentSeborrheic Dermatitis1
4TerminatedTreatmentAtopic Dermatitis (AD)1
3Active Not RecruitingTreatmentAtopic Dermatitis (AD)1
3CompletedTreatmentAtopic Dermatitis (AD)3
3RecruitingTreatmentAtopic Dermatitis (AD)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
OintmentTopical2 % w/w
OintmentTopical20 mg/1g
OintmentCutaneous
OintmentCutaneous20 mg/g
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8039451Yes2011-10-182026-12-11US flag
US8501712Yes2013-08-062027-08-16US flag
US8168614Yes2012-05-012030-07-20US flag
US9682092Yes2017-06-202027-08-16US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsolubleFDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.0234 mg/mLALOGPS
logP2.6ALOGPS
logP3.34ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)8.95ChemAxon
pKa (Strongest Basic)-3.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area62.48 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity65.6 m3·mol-1ChemAxon
Polarizability25.9 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9563
Blood Brain Barrier+0.9383
Caco-2 permeable-0.5845
P-glycoprotein substrateNon-substrate0.547
P-glycoprotein inhibitor INon-inhibitor0.8845
P-glycoprotein inhibitor IINon-inhibitor0.8936
Renal organic cation transporterNon-inhibitor0.6515
CYP450 2C9 substrateNon-substrate0.7986
CYP450 2D6 substrateNon-substrate0.7423
CYP450 3A4 substrateNon-substrate0.6599
CYP450 1A2 substrateInhibitor0.5611
CYP450 2C9 inhibitorNon-inhibitor0.6637
CYP450 2D6 inhibitorNon-inhibitor0.706
CYP450 2C19 inhibitorNon-inhibitor0.5344
CYP450 3A4 inhibitorNon-inhibitor0.8253
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.771
Ames testAMES toxic0.5445
CarcinogenicityNon-carcinogens0.8567
BiodegradationNot ready biodegradable0.9645
Rat acute toxicity2.4979 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7405
hERG inhibition (predictor II)Inhibitor0.5739
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

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Gene Name
PDE4A
Uniprot ID
P27815
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4A
Molecular Weight
98142.155 Da
References
  1. Freund YR, Akama T, Alley MR, Antunes J, Dong C, Jarnagin K, Kimura R, Nieman JA, Maples KR, Plattner JJ, Rock F, Sharma R, Singh R, Sanders V, Zhou Y: Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center. FEBS Lett. 2012 Sep 21;586(19):3410-4. doi: 10.1016/j.febslet.2012.07.058. Epub 2012 Jul 25. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging f...
Gene Name
PDE4B
Uniprot ID
Q07343
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4B
Molecular Weight
83342.695 Da
References
  1. Freund YR, Akama T, Alley MR, Antunes J, Dong C, Jarnagin K, Kimura R, Nieman JA, Maples KR, Plattner JJ, Rock F, Sharma R, Singh R, Sanders V, Zhou Y: Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center. FEBS Lett. 2012 Sep 21;586(19):3410-4. doi: 10.1016/j.febslet.2012.07.058. Epub 2012 Jul 25. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Gene Name
PDE4C
Uniprot ID
Q08493
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4C
Molecular Weight
79900.795 Da
References
  1. Freund YR, Akama T, Alley MR, Antunes J, Dong C, Jarnagin K, Kimura R, Nieman JA, Maples KR, Plattner JJ, Rock F, Sharma R, Singh R, Sanders V, Zhou Y: Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center. FEBS Lett. 2012 Sep 21;586(19):3410-4. doi: 10.1016/j.febslet.2012.07.058. Epub 2012 Jul 25. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Ubiquitin protein ligase binding
Specific Function
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Gene Name
PDE4D
Uniprot ID
Q08499
Uniprot Name
cAMP-specific 3',5'-cyclic phosphodiesterase 4D
Molecular Weight
91114.1 Da
References
  1. Freund YR, Akama T, Alley MR, Antunes J, Dong C, Jarnagin K, Kimura R, Nieman JA, Maples KR, Plattner JJ, Rock F, Sharma R, Singh R, Sanders V, Zhou Y: Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center. FEBS Lett. 2012 Sep 21;586(19):3410-4. doi: 10.1016/j.febslet.2012.07.058. Epub 2012 Jul 25. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da

Drug created on October 21, 2007 22:24 / Updated on June 23, 2021 06:08