A conformationally constrained inhibitor with an enhanced potency for β-tryptase and stability against semicarbazide-sensitive amine oxidase (SSAO)

A novel β-tryptase inhibitor with a basic benzylamine P1 group, a piperidine-amide linker, and a substituted indole P4 group was discovered. A substitution at 4-indole position was introduced to constrain the conformational flexibility of the inhibitor to the bioactive conformation exhibited by X-ray structures so that entropic penalty was decreased. More importantly, this constrained conformation limited the accessibility of this molecule to anti-targets, especially SSAO, so that an enhanced metabolic profile was achieved.

Graphical abstractConformationally constrained β-tryptase inhibitor.Figure optionsDownload full-size imageDownload as PowerPoint slide