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Publication Abstract from PubMed

The use of an interleukin beta 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-IL1beta into active IL-1beta, 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.

Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne.,Fournier JF, Clary L, Chambon S, Dumais L, Harris CS, Millois C, Pierre R, Talano S, Thoreau E, Aubert J, Aurelly M, Bouix-Peter C, Brethon A, Chantalat L, Christin O, Comino C, El-Bazbouz G, Ghilini AL, Isabet T, Lardy C, Luzy AP, Mathieu C, Mebrouk K, Orfila D, Pascau J, Reverse K, Roche D, Rodeschini V, Hennequin LF J Med Chem. 2018 Apr 24. doi: 10.1021/acs.jmedchem.8b00067. PMID:29648825^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.