Expanding the Chemical Space of Drug-like Passerini Compounds: Can alpha-Acyloxy Carboxamides Be Considered Hard Drugs?
ACS MEDICINAL CHEMISTRY LETTERS(2022)
Abstract
With their three points of diversity, alpha-acyloxy carboxamides, which are accessible with the Passerini reaction, provide heterogeneity for the preparation of libraries of putative active agents or intermediates used for the formation of more complex structures. If on the one hand the presence of a hydrolyzable ester function has been exploited to design both prodrugs and soft drugs, on the other hand medicinal chemists are reluctant to use this skeleton to prepare hard drugs. Herein we investigated whether the stability of the ester could be controlled, leading to the formation of hydrolytically stable alpha-acyloxy carboxamides. When the group directly attached to the ester moiety (R-3) is an ortho-substituted or ortho,ortho'-disubstituted aromatic ring, alpha-acyloxy carboxamides are stable. In human liver but not in rodents, due to the different expression of esterases, the ester functionis also stable toward hydrolysis when the R-1 group is a bulky substituent regardless of the nature of the R-3 substituent.
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Key words
Passerini reaction,alpha-acyloxy carboxamides,metabolism,prodrug,soft drug,hard drug
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