The target of Crisaborole (AN2728) is phosphodiesterase 4 (PDE4)[1]
The target of Crisaborole (AN2728) is phosphodiesterase 4 (PDE4) [2]

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].

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Crisaborole (AN2728) exhibits potent inhibitory activity against PDE4 and suppresses the release of cytokines. It was identified through screening a series of phenoxy benzoxaboroles for PDE4 inhibitory activity and cytokine release inhibition[1]
Crisaborole (AN2728) shows in vitro activity by inhibiting PDE4 enzyme activity, which in turn leads to the suppression of the release of pro-inflammatory cytokines including TNFα, IL-12, and IL-23[2]

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].

A series of phenoxy benzoxaborole compounds were synthesized, and Crisaborole (AN2728) was among them. The enzyme activity assay for PDE4 inhibition was conducted by incubating the compound with PDE4 enzyme and the corresponding substrate. The reaction system was maintained under appropriate conditions, and the inhibitory effect of Crisaborole (AN2728) on PDE4 activity was evaluated by detecting changes in substrate consumption or product formation. Through this assay, Crisaborole (AN2728) was confirmed to have potent PDE4 inhibitory activity[1]

Cell-based assays were performed to evaluate the effect of Crisaborole (AN2728) on cytokine release. U937 cells were used as the experimental cell model. The cells were treated with Crisaborole (AN2728) at appropriate concentrations, and a control group without the compound treatment was set up. After incubation for a certain period, the culture supernatant was collected, and the levels of released cytokines were detected using relevant detection methods. The results showed that Crisaborole (AN2728) could suppress cytokine release[1]

Formulated in 1% w/v carboxymethylcellulose (CMC); 0, 30, 100, or 300 mg/kg/day; Oral
Male and female (325 each) Crl:CD1(ICR) mice

Absorption, Distribution and Excretion
Twice-daily topical application achieves systemic concentrations of criborrox after 8 days. Its low systemic absorption rate results in a low risk of systemic side effects. Metabolites are primarily excreted via the kidneys. Metabolisms/Metabolites Criborrox is primarily metabolized into inactive metabolites. The main metabolite, 5-(4-cyanophenoxy)-2-hydroxybenzyl alcohol (metabolite 1), is generated through hydrolysis; this metabolite is further metabolized into downstream metabolites, among which 5-(4-cyanophenoxy)-2-hydroxybenzoic acid (metabolite 2) is also a main metabolite, generated through oxidation.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information regarding the topical use of criborrox during lactation. Due to the lack of relevant information, some experts advise breastfeeding women to avoid using this medication. Generally, medications applied to the mother's skin are unlikely to affect a breastfeeding infant unless applied to the nipple or other areas where the infant can directly ingest the medication. The product label does not prohibit the use of criborrox by breastfeeding women.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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Protein Binding
According to an in vitro study, criborrox binds to human plasma proteins at a rate of 97%.

[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 belongs to the benzoxoborane class of compounds, with the chemical formula 5-hydroxy-1,3-dihydro-2,1-benzoxoborane, in which the hydrogen atom on the phenolic hydroxyl group is replaced by a 4-cyanophenyl group. It is a phosphodiesterase IV inhibitor used to treat mild to moderate atopic dermatitis in children and adults. Crisaborole has a dual role as a phosphodiesterase IV inhibitor, an anti-psoriasis drug, and a nonsteroidal anti-inflammatory drug (NSAID). It is a benzoxoborane compound belonging to the aromatic ether and nitrile class of compounds. Crisaborole is a novel oxoborane compound approved by the U.S. Food and Drug Administration (FDA) on December 14, 2016, under the brand name Eucrisasa, for the treatment of mild to moderate atopic dermatitis. This NSAID effectively improves the severity of the condition in patients aged 2 years and older, reduces the risk of infection, and alleviates signs and symptoms. It reduces local skin inflammation, prevents further deterioration of the condition, and has a good safety profile. Its structure contains boron atoms, which facilitates drug penetration into the skin and binding to the bimetallic center of phosphodiesterase 4 (PDE4). Currently, it is being developed as a topical treatment for psoriasis.
Criborone is a phosphodiesterase 4 inhibitor. The mechanism of action of criborone is as a phosphodiesterase 4 inhibitor.
Drug Indications
Suitable for the topical treatment of mild to moderate atopic dermatitis in patients aged 2 years and older.
FDA Label
Staquis is indicated for the treatment of mild to moderate atopic dermatitis in adults and children aged 2 years and older with an affected body surface area (BSA) ≤ 40%.
Treatment of Atopic Dermatitis
Mechanism of Action
Criborone inhibits PDE4, leading to elevated levels of cyclic adenosine monophosphate (cAMP). Increased intracellular cAMP levels can inhibit the NF-κB pathway and suppress the release of pro-inflammatory mediators such as TNF-α and various interleukins, which play a key role in the pathogenesis of psoriasis and atopic dermatitis. Inhibition of downstream effects in different cell types may explain the therapeutic effect of crisaborole in immune-mediated skin diseases.

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Pharmacodynamics
Crisaborole has broad-spectrum anti-inflammatory activity and mainly targets phosphodiesterase 4 (PDE4), which is a key regulator of the production of inflammatory cytokines. Since this enzyme is expressed in keratinocytes and immune cells, crisaborole has anti-inflammatory effects on almost all inflammatory cells. Topical application of this drug can enhance its localization in the skin, and its anti-inflammatory activity is in the low micromolar concentration range, thus having good efficacy.

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Crisaborole (AN2728) is a novel boron-containing benzoxoxabenoid derivative anti-inflammatory drug. It is being developed for the treatment of psoriasis and atopic dermatitis[1]. Cytokines are considered key factors in maintaining the inflammatory process of psoriasis and atopic dermatitis. Crisaborole (AN2728) is a topical anti-inflammatory compound developed by Anacor Pharmaceuticals Inc. Its mechanism of action is to inhibit PDE4 activity, thereby inhibiting the release of pro-inflammatory cytokines such as TNFα, IL-12 and IL-23. As of the time of this publication, three Phase Ib clinical trials, one Phase IIa clinical trial and one Phase IIb clinical trial of crisaborole (AN2728) for the treatment of psoriasis have been completed. The compound is currently in the Phase II clinical trial stage for the treatment of atopic dermatitis (at that time, there was no data for this indication). The results of the clinical trials showed that the compound had a significant effect on efficacy indicators, and its efficacy was comparable to that of the positive control group, indicating that it has good therapeutic potential. However, larger-scale trials are still needed to evaluate its long-term safety and clarify its broad application prospects [2].

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.)