3057-26-9Relevant articles and documents
Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne
Fournier, Jean-Fran?ois,Clary, Laurence,Chambon, Sandrine,Dumais, Laurence,Harris, Craig Steven,Millois, Corinne,Pierre, Romain,Talano, Sandrine,Thoreau, étienne,Aubert, Jérome,Aurelly, Michèle,Bouix-Peter, Claire,Brethon, Anne,Chantalat, Laurent,Christin, Olivier,Comino, Catherine,El-Bazbouz, Ghizlane,Ghilini, Anne-Laurence,Isabet, Tatiana,Lardy, Claude,Luzy, Anne-Pascale,Mathieu, Céline,Mebrouk, Kenny,Orfila, Danielle,Pascau, Jonathan,Reverse, Kevin,Roche, Didier,Rodeschini, Vincent,Hennequin, Laurent Fran?ois
supporting information, p. 4030 - 4051 (2018/05/23)
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.
One-pot Synthesis of Protected Alkylhydrazines from Acetals and Ketals. Scope and Limitations
Mastitski, Anton,Niinepuu, Siret,Haljasorg, T?iv,J?rv, Jaak
, p. 490 - 498 (2015/11/09)
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Benzyloxy(4-substituted benzyloxy)carbenes. Generation from oxadiazolines and fragmentation to radical pairs in solution
Merkley,Warkentin
, p. 942 - 949 (2007/10/03)
Thermolysis of 2,2-dibenzyloxy-5,5-dimethyl-Δ3-1,3,4-oxadiazoline in benzene at 110°C leads to dibenzyloxycarbene. The carbene was trapped with tert-butyl alcohol to afford dibenzyl-tert-butyl orthoformate. In the absence of a trapping agent for the carbene, it fragmented to benzyloxycarbonyl and benzyl radicals, as shown by trapping the latter with TEMPO. In the absence of both TEMPO and tert-butyl alcohol, the radicals were partitioned between coupling to benzyl phenylacetate and decarboxylation, with subsequent formation of bibenzyl. The preferred sense of fragmentation of the analogous carbenes from benzyloxy-(p-substituted-benzyloxy)carbenes was determined by comparing the yields of the two possible esters, ArCH2O(CO)CH2Ph and PhCH2O(CO)CH2Ar. It was found that an electron-withdrawing group in the para position favoured fragmentation to the benzylic radical containing that group. A Hammett plot of the data gave a best fit with σ- substituent constants (r = 0.994, ρ((PhH, 110°C) = 0.7)) suggesting that the fragmentation involves charge separation in the sense that increases electron density on the group that is becoming a benzylic radical and decreases electron density on the carbonyl group that is becoming the benzyloxycarbonyl radical.
