The arginine mimicking β-amino acid β³hPhe(3-H₂N-CH₂) as S1 ligand in cyclotheonamide-based β-tryptase inhibitors.

β-Tryptase, a mast-cell specific serine protease with trypsin-like activity, has emerged in the last years as a promising novel therapeutic target in the field of allergic inflammation. Recently, we have developed a potent and selective β-tryptase inhibitor based on the natural product cyclotheonamide E4 by implementing a basic P3 residue that addresses the determinants of the extended substrate specificity of β-tryptase. To further improve the affinity/selectivity profile of this lead structure, we have now investigated β-homo-3-aminomethylphenylalanine as S1 ligand. In contrast to the corresponding β-homo amino acids derived from lysine or arginine, we demonstrate that this particular basic β-homo amino acid is a privileged S1 ligand for the development of β-tryptase inhibitors. Besides affinity, selectivity and reduced basicity, these novel cyclotheonamide E4 analogs show excellent stability in human plasma and serum.