title: The arginine mimicking β-amino acid β³hPhe(3-H₂N-CH₂) as S1 ligand in cyclotheonamide-based β-tryptase inhibitors.
abstract: 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.
authors: Fakultät für Chemie, Universität Bielefeld, Universitätsstr. 25, D-33615 Bielefeld, Germany.
authors: Dennis
authors: D
authors: Janke
authors: Christian P
authors: CP
authors: Sommerhoff
authors: Norbert
authors: N
authors: Schaschke
mesh_terms: D001120:Arginine / Q000737:chemistry*; D040761:Biomimetic Materials / Q000737:chemistry; D004355:Drug Stability; D006801:Humans; D008024:Ligands; D010456:Peptides, Cyclic / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D015842:Serine Proteinase Inhibitors / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D053802:Tryptases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D008024:Ligands; D010456:Peptides, Cyclic; D015842:Serine Proteinase Inhibitors; C452833:cyclotheonamide E4; D010649:Phenylalanine; D001120:Arginine; D053802:Tryptases