Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne
| Autor: | Didier M. Roche, Danielle Orfila, Ghizlane El-Bazbouz, Laurence Dumais, Laurent F. Hennequin, Céline Mathieu, Michèle Aurelly, Jerome Aubert, Claude Lardy, Etienne Thoreau, Anne-Pascale Luzy, Claire Bouix-Peter, Kenny Mebrouk, T. Isabet, Jean-François Fournier, Kevin Reverse, Catherine Comino, Corinne Millois, Anne-Laurence Ghilini, Jonathan Pascau, Sandrine Talano, Anne Brethon, Craig S. Harris, Romain Pierre, Sandrine Chambon, Laurence Clary, Olivier Christin, Laurent Chantalat, Vincent Rodeschini |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Protein Conformation Administration Topical medicine.medical_treatment Caspase 1 Drug design Pharmacology 01 natural sciences Cell Line Mice 03 medical and health sciences chemistry.chemical_compound Acne Vulgaris Drug Discovery medicine Animals Humans Tissue Distribution Caspase Acne Protease biology 010405 organic chemistry Uracil medicine.disease Caspase Inhibitors 0104 chemical sciences 030104 developmental biology chemistry Drug Design Solvents biology.protein Molecular Medicine Pharmacophore Phototoxicity |
| Zdroj: | Journal of Medicinal Chemistry. 61:4030-4051 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b00067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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