370875-23-3Relevant 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.
Synthesis and stability evaluation of novel peptidomimetic Caspase-1 inhibitors for topical application
Chambon, Sandrine,Talano, Sandrine,Millois, Corinne,Dumais, Laurence,Pierre, Romain,Tomas, Loic,Mathieu, Céline,Ghilini, Anne-Laurence,Vanthuyne, Nicolas,Reverse, Kevin,Brethon, Anne,Rodeschini, Vincent,Comino, Catherine,Mouis, Grégoire,El-Bazbouz, Ghizlane,Clary, Laurence,Fournier, Jean-Fran?ois,Bouix-Peter, Claire,Harris, Craig S.,Hennequin, Laurent F.
, p. 4805 - 4822 (2018/08/06)
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.
Prodrug of an ice inhibitor
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Page/Page column 16, (2016/11/24)
This invention describes an ICE inhibitor prodrug (I) having good bioavailability. Compound I is useful for treating IL-1 mediated diseases such as rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, inflammatory periton
Synthesis and evaluation of novel 8,6-fused bicyclic peptidomimetic compounds as interleukin-1b converting enzyme inhibitors
O'Neil, Steven V.,Wang, Yili,Laufersweiler, Michael C.,Oppong, Kofi A.,Soper, David L.,Wos, John A.,Ellis, Christopher D.,Baize, Mark W.,Bosch, Gregory K.,Fancher, Amy N.,Lu, Wei,Suchanek, Maureen K.,Wang, Richard L.,De, Biswanath,Demuth Jr., Thomas P.
, p. 5434 - 5438 (2007/10/03)
Two novel 8,6-fused bicyclic peptidomimetic ring systems were synthesized utilizing olefin metathesis as the key reaction for the formation of the eight-membered ring. Both peptidomimetic scaffolds were further elaborated into potent ICE inhibitors, with
C-terminal modified oxamyl dipeptides as inhibitors of the ICE-ced-3 family of cysteine proteases
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, (2008/06/13)
This invention is directed to novel oxamyl dipeptide ICE/ced-3 family inhibitor compounds. The invention is also directed to pharmaceutical compositions containing these compounds, as well as to the use of such compositions in the treatment of patients su
