Identification

Name
Crisaborole
Accession Number
DB05219
Type
Small Molecule
Groups
Approved, Investigational
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
Synonyms
Not Available
External IDs
AN-2728 / AN2728
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EucrisaOintment20 mg/1gTopicalPfizer Laboratories Div Pfizer Inc.2017-01-30Not applicableUs
Categories
UNII
Q2R47HGR7P
CAS number
906673-24-3
Weight
Average: 251.05
Monoisotopic: 251.075373
Chemical Formula
C14H10BNO3
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

Pharmacology

Indication

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

Associated Conditions
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
Human
UcAMP-specific 3',5'-cyclic phosphodiesterase 4B
inhibitor
Human
UcAMP-specific 3',5'-cyclic phosphodiesterase 4C
inhibitor
Human
UcAMP-specific 3',5'-cyclic phosphodiesterase 4D
inhibitor
Human
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
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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AceclofenacThe metabolism of Aceclofenac can be decreased when combined with Crisaborole.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Crisaborole.
Acetyl sulfisoxazoleThe metabolism of Acetyl sulfisoxazole can be decreased when combined with Crisaborole.
AlmotriptanThe metabolism of Almotriptan can be decreased when combined with Crisaborole.
AlosetronThe metabolism of Alosetron can be decreased when combined with Crisaborole.
AminophenazoneThe metabolism of Aminophenazone can be decreased when combined with Crisaborole.
AmitriptylineThe metabolism of Amitriptyline can be decreased when combined with Crisaborole.
AmodiaquineThe serum concentration of Amodiaquine can be increased when it is combined with Crisaborole.
AmodiaquineThe metabolism of Amodiaquine can be decreased when combined with Crisaborole.
AmprenavirThe metabolism of Amprenavir can be decreased when combined with Crisaborole.
Food Interactions
Not Available

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. [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
KEGG Drug
D10873
PubChem Compound
44591583
PubChem Substance
175426957
ChemSpider
24701949
BindingDB
50277665
ChEBI
134677
ChEMBL
CHEMBL484785
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Crisaborole
FDA label
Download (185 KB)
MSDS
Download (42.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentPsoriasis1
1RecruitingHealth Services ResearchMild to Moderate Atopic Dermatitis1
2CompletedTreatmentPsoriasis3
2RecruitingTreatmentMorphoea1
3Not Yet RecruitingTreatmentAtopic Dermatitis (AD)1
4Not Yet RecruitingTreatmentSeborrheic Dermatitis1
4RecruitingTreatmentAtopic Dermatitis (AD)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
OintmentTopical20 mg/1g
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8039451No2006-06-112026-06-11Us
US8501712No2007-02-162027-02-16Us
US8168614No2010-01-202030-01-20Us
US9682092No2007-02-162027-02-16Us

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

Taxonomy

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
Diaryl ether / Phenoxy compound / Benzonitrile / Phenol ether / Monocyclic benzene moiety / Benzenoid / Boronic acid ester / 1,2-oxaborole derivative / Boronic acid derivative / Oxacycle
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not 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 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. [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 un...
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 un...
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 un...
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 un...
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 August 02, 2018 05:29