Identification
NameCrisaborole
Accession NumberDB05219
TypeSmall Molecule
GroupsApproved
Description

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.

Structure
Thumb
SynonymsNot Available
External IDs AN-2728 / AN2728
Product Ingredients Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EucrisaOintment20 mg/gTopicalAnacor Pharmaceuticals, Inc.2017-01-30Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Categories
UNIIQ2R47HGR7P
CAS number906673-24-3
WeightAverage: 251.05
Monoisotopic: 251.075373
Chemical FormulaC14H10BNO3
InChI KeyUSZAGAREISWJDP-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
Pharmacology
Indication

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

Structured Indications
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.

TargetKindPharmacological actionActionsOrganismUniProt ID
cAMP-specific 3',5'-cyclic phosphodiesterase 4AProteinunknown
inhibitor
HumanP27815 details
cAMP-specific 3',5'-cyclic phosphodiesterase 4BProteinunknown
inhibitor
HumanQ07343 details
cAMP-specific 3',5'-cyclic phosphodiesterase 4CProteinunknown
inhibitor
HumanQ08493 details
cAMP-specific 3',5'-cyclic phosphodiesterase 4DProteinunknown
inhibitor
HumanQ08499 details
Related Articles
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 distributionNot 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 lifeNot Available
ClearanceNot Available
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.

Affected organisms
  • Humans and other mammals
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions Not Available
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
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. [PubMed:27417017 ]
  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. [PubMed:28492291 ]
  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. [PubMed:27335049 ]
  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. [PubMed:24852768 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (185 KB)
MSDSDownload (42.3 KB)
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentPsoriasis1
2CompletedTreatmentPsoriasis3
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
OintmentTopical20 mg/g
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8039451 No2006-06-112026-06-11Us
US8501712 No2007-02-162027-02-16Us
US8168614 No2010-01-202030-01-20Us
US9682092 No2007-02-162027-02-16Us
Properties
StateSolid
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
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MSNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganic oxygen compounds
ClassOrganooxygen compounds
Sub ClassEthers
Direct ParentDiarylethers
Alternative ParentsPhenoxy compounds / Phenol ethers / Benzonitriles / Oxaborole derivatives / Boronic acid esters / Oxacyclic compounds / Organic metalloid salts / Nitriles / Organometalloid compounds / Hydrocarbon derivatives
SubstituentsDiaryl ether / Phenoxy compound / Benzonitrile / Phenol ether / Monocyclic benzene moiety / Benzenoid / Boronic acid ester / 1,2-oxaborole derivative / Boronic acid derivative / Oxacycle
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available

Targets

Kind
Protein
Organism
Human
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. [PubMed:22841723 ]
Kind
Protein
Organism
Human
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 from antidepressants to antiasthmatic and anti-inflammatory agents.
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. [PubMed:22841723 ]
Kind
Protein
Organism
Human
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. [PubMed:22841723 ]
Kind
Protein
Organism
Human
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. [PubMed:22841723 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
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 N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Uniprot Name:
Cytochrome P450 1A2
Molecular Weight:
58293.76 Da
Kind
Protein
Organism
Human
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 unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,4-cineole 2-exo-monooxygenase.
Gene Name:
CYP2B6
Uniprot ID:
P20813
Uniprot Name:
Cytochrome P450 2B6
Molecular Weight:
56277.81 Da
Kind
Protein
Organism
Human
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 unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme...
Gene Name:
CYP2C8
Uniprot ID:
P10632
Uniprot Name:
Cytochrome P450 2C8
Molecular Weight:
55824.275 Da
Kind
Protein
Organism
Human
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 unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Uniprot Name:
Cytochrome P450 2C9
Molecular Weight:
55627.365 Da
Drug created on October 21, 2007 16:24 / Updated on September 01, 2017 11:24