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

Sandrine Chambon (1) , Sandrine Talano (1) , Corinne Millois (1) , Laurence Dumais (1) , Romain Pierre (1) , Loïc Tomas (1) , Céline Mathieu (1) , Anne-Laurence Ghilini (1) , Nicolas Vanthuyne (2) , Kevin Reverse (1) , Anne Brethon (3) , Vincent Rodeschini (4) , Catherine Comino (1) , Gregoire Mouis (1) , Ghizlane El-Babouz (1) , Laurence Clary (1) , Jean-François Fournier (1) , Claire Bouix-Peter (1) , Craig S. Harris (1) , Laurent F. Hennequin (1)

1 Nestle Skin Health GALDERMA R&D
2 ISM2 - Institut des Sciences Moléculaires de Marseille
3 edelris
4 edelris

During our search for topically-active Caspase-1 inhibitors, we identified a novel class of potent in-hibitors 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.

Mots clés: Caspase-1 inhibitors 1; 3; 5-Trisubstitued uracil Peptidomimetics Topical application Excipient stability Chiral stability

Domaines: Chimie

Sandrine Chambon, Sandrine Talano, Corinne Millois, Laurence Dumais, Romain Pierre, et al.. Synthesis and stability evaluation of novel peptidomimetic Caspase-1 inhibitors for topical application. Tetrahedron, 2018, 74 (37), pp.4805-4822. ⟨10.1016/j.tet.2018.07.029⟩. ⟨hal-02092020⟩