Succinic acid amides as P2–P3 replacements for inhibitors of interleukin-1β converting enzyme (ICE or caspase 1)

Succinic acid amides have been found to be effective P2–P3 scaffold replacements for peptidic ICE inhibitors. Heteroarylalkyl fragments occupying the P4 position provided access to compounds with nM affinities. Utilization of an acylal prodrug moiety was required to overcome biopharmaceutical issues which led to the identification of 17f, a potential clinical candidate.

Graphical abstractSuccinic acid amides have been found to be effective P2–P3 scaffold replacements. ICE inhibitors based on this framework were synthesized and evaluated and the in vivo active ICE inhibitor 17f is reported.Figure optionsDownload full-size imageDownload as PowerPoint slide