1072845-47-6Relevant articles and documents
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)
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.
Synthesis and utilization of chiral α-methylated α-amino acids with a carboxyalkyl side chain in the design of novel Grb2-SH2 peptide inhibitors free of phosphotyrosine
Long, Ya-Qiu,Xue, Ting,Song, Yan-Li,Liu, Zu-Long,Huang, Shao-Xu,Yu, Qiang
experimental part, p. 6371 - 6380 (2009/10/17)
The growth factor receptor-bound protein 2 (Grb2) is an SH2 domain-containing docking module that represents an attractive target for anticancer therapeutic intervention. To improve the potency and bioavailability of the Grb2-SH2 inhibitors, the chiral α-methyl-α-carboxyalkyl amino acid [(α-Me)Aa] was designed to cover dual structural and functional features separately contributed by 1-aminocyclohexanecarboxylic acid (Ac6c) and α-aminoadipic acid (Adi) in position Y + 1. The enantiopure L(or D)-(α-Me)Aa bearing various chain length carboxylalkyl side chain was conveniently synthesized by an optimized oxazolidinone methodology. The incorporation of (S)-(α-Me)Aa into the non-pTyr-containing peptide framework with a 5-amino acid sequence binding motif of X-2-Leu- (3′-substituted-Tyr)0-X+1-Asn really improved the inhibitory activity, affording potent (R)-sulfoxide-bridged cyclic and an open-chain series of pentapeptide inhibitors of Grb2-SH2 domain (IC50 = 1.1-5.8 μM). More significantly, these (α-Me)Aa incorporated peptide inhibitors showed excellent activities in inhibiting the growth of erbB2-dependent MDA-MB-453 tumor cell lines with low micromolar IC50 values, owing to the reduced peptidic nature and absence of pTyr or pTyr mimetics.
