New substrate analogue furin inhibitors derived from 4-amidinobenzylamide

作者：Becker Gero L; Hardes Kornelia; Steinmetzer Torsten^*

来源：Bioorganic & Medicinal Chemistry Letters, 2011, 21(16): 4695-4697.

DOI：10.1016/j.bmcl.2011.06.091

• Furin
• Proprotein convertase
• Protease inhibitor
• Peptidomimetic inhibitor
• Serine protease

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 2 nM, 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.

• 出版日期2011-8-15