Potent Antipsoriatic Agents: A Facile Preparation of Acylated Derivatives from Dithranol in a Mild Basic Reaction

Liang, Deron; Du, Chun-Jian

doi:10.1002/jccs.200400018

Cited by 1 publication

(1 citation statement)

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“…The preparation of ester co-drugs was not as straightforward as expected due to the reactivity of the C-10 methylene group in 1 . Although the majority of reported dithranol analogs are modified at C-10, a limited number 1- O -mono-substituted and 1,8- O -disubstituted esters have been reported [ 16 , 25 ]. The published synthetic methods failed to yield the anticipated dithranol ester derivatives in our hands, instead yielding C-10 substituted derivatives (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis

2013

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Psoriasis is a common, chronic and relapsing inflammatory skin disease. It affects approximately 2% of the western population and has no cure. Combination therapy for psoriasis often proves more efficacious and better tolerated than monotherapy with a single drug. Combination therapy could be administered in the form of a co-drug, where two or more therapeutic compounds active against the same condition are linked by a cleavable covalent bond. Similar to the pro-drug approach, the liberation of parent moieties post-administration, by enzymatic and/or chemical mechanisms, is a pre-requisite for effective treatment. In this study, a series of co-drugs incorporating dithranol in combination with one of several non-steroidal anti-inflammatory drugs, both useful for the treatment of psoriasis, were designed, synthesized and evaluated. An ester co-drug comprising dithranol and naproxen in a 1:1 stoichiometric ratio was determined to possess the optimal physicochemical properties for topical delivery. The co-drug was fully hydrolyzed in vitro by porcine liver esterase within four hours. When incubated with homogenized porcine skin, 9.5% of the parent compounds were liberated after 24 h, suggesting in situ esterase-mediated cleavage of the co-drug would occur within the skin. The kinetics of the reaction revealed first order kinetics, Vmax = 10.3 µM·min−1 and Km = 65.1 µM. The co-drug contains a modified dithranol chromophore that was just 37% of the absorbance of dithranol at 375 nm and suggests reduced skin/clothes staining. Overall, these findings suggest that the dithranol-naproxen co-drug offers an attractive, novel approach for the treatment of psoriasis.

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Section: Resultsmentioning

confidence: 99%