Crisaborole (AN-2728) has IC50 values of 0.49, 0.54, 0.61, 0.83, 2.4, and 5.3 μM and inhibits PDE4, TNF-α, IL-2, IFN-γ, IL-5, and IL-10. The most effective compound against the PDE4 catalytic domain is crisaborole (AN-2728), however it also exhibits inhibition against PDE1A3, PDE3Cat, and PDE7A1. With IC50 values of 6.1, 6.4, 0.11, and 0.73 μM, crisaborole (AN-2728) inhibits PDE isozymes PDE1A3, PDE3Cat, PDE4Cat, and PDE7A1[1]. Crystallography shows that benzoxaboroles' affinity for PDE4 is increased when they engage with the hydrophobic pocket in the PDE4 catalytic domain. These benzoxaboroles significantly reduce the release of cytokines linked to AD and Ps[2]. Crisaborole (AN-2728) is an anti-inflammatory substance with boron that is used topically. It works by inhibiting PDE4 activity, which in turn prevents the release of TNFalpha, IL-12, IL-23, and other cytokines[3].

After dosing at 1 mg/ear×2, crisaborole (AN-2728) exhibits a considerable inhibition against the ear edema caused by phorbol ester (78% and 68%, respectively). It is possible that Crisaborole (AN-2728) has good skin penetration and anti-inflammatory activity because the efficacy is similar to that of dexamethasone[1]. According to reports, crisaborole (AN-2728) is well tolerated and exhibits notable impacts on efficacy markers, yielding outcomes similar to those of positive controls in clinical trials[3].

Absorption, Distribution and Excretion
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.
Renal excretion of metabolites is the major route of elimination.

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Metabolism / Metabolites
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.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of topical crisaborole during breastfeeding. Some experts recommend avoiding its use during lactation because of the lack of information. In general, drugs applied to the mother’s skin are unlikely to affect the breastfed infant unless it is applied to the nipple or other area where the infant can directly ingest it. Use of crisaborole in nursing mothers is not contraindicated by the product labeling,
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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

[1]. Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2129-32.

[2]. AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis. Curr Opin Investig Drugs. 2009 Nov;10(11):1236-42.

Crisaborole is a member of the class of benzoxaboroles that is 5-hydroxy-1,3-dihydro-2,1-benzoxaborole in which the phenolic hydrogen has been replaced by a 4-cyanophenyl group. A phosphodiesterase 4 inhibitor that is used for treatment of mild to moderate atopic dermatitis in children and adults. It has a role as a phosphodiesterase IV inhibitor, an antipsoriatic and a non-steroidal anti-inflammatory drug. It is a benzoxaborole, an aromatic ether and a nitrile.
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.
Crisaborole is a Phosphodiesterase 4 Inhibitor. The mechanism of action of crisaborole is as a Phosphodiesterase 4 Inhibitor.

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Drug Indication
Intended for the topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older.
FDA Label
Staquis is indicated for treatment of mild to moderate atopic dermatitis in adults and paediatric patients from 2 years of age with ≤ 40% body surface area (BSA) affected.
Treatment of atopic dermatitis

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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.

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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.

C14H10BNO3

251.05

251.075

906673-24-3

Crisaborole-d4;2268785-42-6

44591583

White to khaki solid powder

1.3±0.1 g/cm3

425.9±55.0 °C at 760 mmHg

211.4±31.5 °C

0.0±1.1 mmHg at 25°C

1.629

1.568

1

4

2

19

361

0

USZAGAREISWJDP-UHFFFAOYSA-N

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

4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)benzonitrile

AN-2728; PF06930164; AN 2728; PF-06930164; AN2728; PF 06930164; trade name: Eucrisa

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.96 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.96 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (9.96 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)