†This paper is dedicated to Prof. Yuichi Sugiyama, Head of the Sugiyama Laboratory at RIKEN Innovation Center (Yokohama, Japan), in recognition of his 70th birthday.
Abstract
Loteprednol etabonate (LE) is the first, highly successful soft corticosteroid (SC) designed using the ‘inactive metabolite’ approach, starting with ∆1-cortienic acid (d-CA). The next generation of SCs based on d-CA was etiprednol dicloacetate (ED). The 17α-dichloroacetyl function serves both as a unique pharmacophore and as the source of the molecule’s softness. Highly potent SCs were designed based on a combination of ED and LE, introducing 6, 9 and 16 substituents in the molecule.
The new 6α, 9α, 16α and β 17α-dichloroacetyl 17β-esters were synthesized from the correspondingly substituted ∆1-cortienic acids. The anti-inflammatory activity was assessed using LPS-induced TNF α-release under various conditions to determine intrinsic activity vs. systemic biological stability. In vivo anti-inflammatory activity was studied in the widely used ovalbumin-sensitized and ovalbumin-challenged Brown Norway rat model.
The 6α or 9α-fluoro substitution produced highly potent corticosteroids, but the 17α-dichloroacetyl substituent provided ‘softness’ in all cases. Local application of these steroids will significantly reduce systemic activity, due to the facile hydrolytic deactivation of these molecules.
A 17α-dichloroacetyl derivative of fluticasone (FLU) is highly potent but much safer than the currently used propionate or furoate ester.