Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne

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.