title: New substrate analogue furin inhibitors derived from 4-amidinobenzylamide.
abstract: 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 K(i) 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.
authors.forename: Gero L
authors.initials: GL
authors.lastname: Becker
authors.forename: Kornelia
authors.initials: K
authors.lastname: Hardes
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045683:Furin / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000578:Amidines; D001593:Benzyl Compounds; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D057786:Peptidomimetics; D045683:Furin