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

Abstract

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.

Trisubstituted push-pull nitro alkenes

“…Second method B can be considered as an analog to method A for the preparation of 3-amino-substituted reviewed structures. 14,28,[34][35][36][37][38] The products 3-alkylamino-2-nitroacrylic esters used to be prepared by nucleophilic vinylic substitution on 3-alkoxy-2-nitroacrylic esters with adequate N-nucleophile. 28 The paper 31 describing reactions with diverse groups of N-nucleophiles and utilizing "one-pot" reaction pathway B depicted in (Scheme 3), was published in 1963.…”

“…The first group contains mostly pyrimidine or pyrimidone derivatives (Scheme 9) that are formed by reactions with ureas and amidines. [13][14][15]18,31,34,59,60 There are also examples of other six-membered heterocycles (pyridine 35 and thiadiazine 61 ) prepared in a similar manner. The second group contains structurally more different products (Scheme 10) that are formed by reaction with usually amino heterocycles as 1,3-binucleophiles.…”

“…Trisubstituted push-pull nitro alkenes are one of the most important compounds of such omitted nitro alkenes group (Figure 1). Disubstituted push-pull nitro alkenes (without another electron acceptor A) undergo formations of heterocycles worse than trisubstituted nitroalkenes as another electron acceptor A can readily react in nucleophilic additions with 1,2-12 or 1,3-binucleophiles 13,14 and nitro group cannot offer such a reaction. The preparation of tetrasubstituted nitroalkenes is less convenient than trisubstituted nitroalkenes in terms of yields, a number of methods, reaction times, temperatures, and toxicity of required reagents.…”

“…The value of this group of compounds can be demonstrated by their utilization as a reagent in the synthesis of biologically active compounds over the years. [14][15][16][17][18][19][20] For instance, they have been used in rational drug design of topically administered caspase 1 inhibitors for the treatment of inflammatory acne, 14 in the synthesis and biological evaluation of pyrimidine derivatives as novel human Pin1 inhibitors in the cancer treatment, 15 and the preparation of scaffolds for the design of Rac1−Tiam1 protein−protein interaction inhibitors 16,17 . Title compounds were also employed in the synthesis of alkaloid meridianin G, 18 and the synthesis of the insect feeding deterrent peramine.…”

Synthesis and stability evaluation of novel peptidomimetic Caspase-1 inhibitors for topical application

“…Inspired by their approach, we set about designing our own cyclic peptidomimetic inhibitors based on scaffolds while preserving the 3 point H-bonding network and the aspartaldehyde warhead (Fig. 2) [7].…”