Concept and Development of a Potent Topical Corticosteroid

Abstract

In a rational approach to identify an ultrapotent compound for the treatment of therapy-resistant dermatoses, Weirich's modification of McKenzie's skin vasoconstriction assay (HVK test) has been used as the essential selection criteria. In a primary phase, a quantitative relationship between the HVK activity of 25 derivatives of corticosterone substituted in various positions of the skeleton, and their lipophilicity (log P) was established. The specific lipophilicity-independent interactions were accounted for by the inclusion of 'indicator variables' into the regression analysis. The highly significant results allowed to localize an optimal log P range and to identify the influence of various substituents. In a next phase, the evidence of the first HVK analysis was refined by considering 28 additional compounds. On the basis of the confirmed facts, six 21-chloro-6α-fluoro compounds were specifically synthesized and submitted to dermatopharmacological testing. Finally, CGP 14458 (= 2l-chloro-6α,9-difluoro-11β-hydroxy-16β-methyl-3,20-dioxopregna-1,4-dien-17α-yl propionate) which was predicted to be the most potent representative of these series, whose synthesis is described in detail, showed indeed to be the most effective compound. Clinical trials with this compound – halobetasol propionate/Ultravate® (ulobetasol/Miracorten®) – confirmed its unique efficacy, especially in the treatment of severe, chronic plaque psoriasis.