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The use of an interleukin β antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1β into active IL-1β, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.

The release of encapsulated carboxyfluorescein (CF) from liposomes made from various fluorinated amido-connected double-chain phosphocholines and their membrane permeability have been investigated at 37 degrees C in buffer and in human serum. These fluorinated membranes and liposomes display lower permeability coefficients and are able to retain more efficiently encapsulated CF than any of their respective conventional counterparts. Several of these liposomes are as effective as the first generation of liposomes based on fluorinated phosphatidylcholines, indicating that the chemical junction (ester/amide) and nature of the unit (glycerol, diaminopropanol, serine, ethanolamine) connecting the hydrophobic chains to the phosphocholine polar head have no significant effect on permeability and CF release. Our results show further that a fluorinated intramembrane layer reduces significantly the permeability of membranes in a liquid-crystalline state, protects the liposomes from the destabilizing effects of serum, and even increases their stability (in terms of dye retention) in serum when the membranes are in the gel state.

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During our search for topically-active Caspase-1 inhibitors, we identified a novel class of potent inhibitors based on a 1,3,5-trisubstituted uracil motif equipped with an L-aspartate semi-aldehyde derived warhead. In the literature, the majority of Caspase-1 inhibitors possessing the same warhead have been designed and evaluated for oral administration as the ethyl acetal pro-drug form. For our topical program, the pro-drug acetal form was not fully hydrolysed in the skin and was unstable in many of our standard topical excipients, therefore, we were obliged to focus on the actual hemiacetal drug form of the molecule during our drug discovery program. Our work focuses on both the synthesis and achiral and chiral stability of the final drug molecules in topical excipients.

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