New substrate analogue furin inhibitors derived from 4-amidinobenzylamide

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 16; pp. 4695 - 4697
• Main Authors: Becker, Gero L., Hardes, Kornelia, Steinmetzer, Torsten
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.08.2011; Elsevier
• Subjects: Amidines - chemical synthesis; Amidines - chemistry; Amidines - pharmacology; amino acids; Analytical, structural and metabolic biochemistry; Benzyl Compounds - chemical synthesis; Benzyl Compounds - chemistry; Benzyl Compounds - pharmacology; Biological and medical sciences; cell culture; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Furin; Furin - antagonists & inhibitors; Hydrolases; Medical sciences; Miscellaneous; Molecular Conformation; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Peptidomimetic inhibitor; Peptidomimetics - chemical synthesis; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Pharmacology. Drug treatments; Proprotein convertase; Protease inhibitor; proteinase inhibitors; Serine protease; Structure-Activity Relationship; Furin; Serine protease; Peptidomimetic inhibitor; Proprotein convertase; Protease inhibitor; Serine endopeptidases; Peptides; Enzyme; Peptidomimetic compound; Tripeptide; Enzyme inhibitor; Guanidines; In vitro; Peptidases; Amidine; Structure activity relation; Hydrolases; Peptide synthesis; Solid phase; Valine derivatives
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.06.091

A series of new peptidomimetic furin inhibitors was synthesized, which was derived from our previously described lead structure phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide (1). Substitution of Val by other amino acid residues revealed several highly potent furin inhibitors with Ki values of less than 2nM, containing guanidinoalanine, Ile, Phe or Tyr in the P3 position. The replacement of the P2 Arg by Lys was also well accepted, whereas the incorporation of d-amino acids at various positions resulted in poor inhibitors. The use of the 4-amidinobenzylamide group provides convenient synthetic access to stable proprotein convertase inhibitors and derivatives as biochemical tools and for further studies in cell culture.