Description
Crisaborole is a phosphodiesterase- 4 (PDE4) inhibitor that was approved by FDA on December 14, 2016 as Eucrisa, a topical treatment of for mild to moderate atopic dermatitis (AD) in patients aged two years and older. The drug, which was developed by Anacor Pharmaceuticals and later acquired and marketed by Pfizer, is delivered as a 2% ointment, which is applied topically. Its structure contains a boron atom, which facilitates skin penetration and binding to the bimetal center of the phosphodiesterase 4 enzyme. The unique employment of boron within the chemical structure of the drug is designed to enable selective engagement of PDE4 (an enzyme involved in the conversion of cAMP into AMP, which signals for downstream inflammatory events), effective penetration of the drug through human skin, and rapid clearance to limit systemic circulation.
Uses
A series of phenoxy benzoxaboroles were synthesized and screened for their inhibitory activity against PDE4 and cytokine release. 5-(4-Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2728) showed potent activity both in vitro and in vivo. AN2728 is being studied as an anti-inflammatory agent.
Definition
ChEBI: 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of the class of benzoxaboroles that is 5-hydroxy-1,3-dihydro-2,1-benzoxaborole in which the phenolic hydrogen has been replaced by a 4-cyanophenyl group.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.
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Biochem/physiol Actions
Crisaborole is a non-steroidal anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor. Crisaborole has an IC50 value of 490 nM for PDE4 with similar IC50 values for release of cytokines TNF-α, IL-2, and IFN-γ, and shows little inhibition against other PDE isozymes. Crisaborole has been approved as a topical treatment for atopic dermatitis.
Side effects
EUCRISA may cause side effects.
Allergic reactions. EUCRISA may cause allergic reactions at or near the application site. These can be serious and may include hives, itching, swelling, and redness.
www.eucrisa.com
Synthesis
Several disclosures describing synthetic approaches to
ethereal boron-containing anti-inflammatory compounds have
been published by Anacor. Commercially available bromobenzaldehyde
134 was protected as the corresponding acetal upon
subjection to warm ethylene glycol in the presence of catalytic
p-toluenesulfonic acid. This was followed by nucleophilic
aromatic substitution involving 4-fluorobenzonitrile and subsequent
acetal deprotection to furnish diaryl ether 136.
Although multiple approaches to crisaborole have been
reported from this intermediate diaryl ether 136, the
published literature approach involves the following sequence:
reduction of the aldehyde with sodium borohydride followed
by THP protection to furnish bromobenzene 137, which then
underwent lithium-halogen exchange prior to quenching with
triisopropyl borate and acidification to arrive at crisaborole
(XIII). Alternatively, patents from Anacor describe a general
approach employing a Miyaura coupling of 136, enabling the
installation of the corresponding pincacol borane, which could
then be exposed to reduction conditions using sodium
borohydride followed by boric acid wash, aqueous workup,
and lyophilization to furnish XIII.
Mode of action
Crisaborole is a Phosphodiesterase 4 Inhibitor. The mechanism of action of crisaborole is as a Phosphodiesterase 4 Inhibitor.
