Structure-based design of a novel series of azetidine inhibitors of the hepatitis C virus NS3/4A serine protease

  • Bioorg Med Chem Lett. 2014 Sep 15;24(18):4444-4449. doi: 10.1016/j.bmcl.2014.08.002.
Christophe Parsy  1 ,  François-René Alexandre  2 ,  Guillaume Brandt  2 ,  Catherine Caillet  2 ,  Sylvie Cappelle  2 ,  Dominique Chaves  2 ,  Thierry Convard  2 ,  Michel Derock  2 ,  Damien Gloux  2 ,  Yann Griffon  2 ,  Lisa Lallos  3 ,  Frédéric Leroy  2 ,  Michel Liuzzi  3 ,  Anna-Giulia Loi  3 ,  Laure Moulat  2 ,  Chiara Musiu  3 ,  Houcine Rahali  2 ,  Virginie Roques  2 ,  Maria Seifer  3 ,  David Standring  3 ,  Dominique Surleraux  2
Affiliations
  • 1. IDENIX Pharmaceuticals, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France. Electronic address: [email protected].
  • 2. IDENIX Pharmaceuticals, 1682 rue de la Valsière, Cap Gamma, BP 50001, 34189 Montpellier Cedex 4, France.
  • 3. IDENIX Pharmaceuticals, 320 Bent Street-4th Floor, Cambridge, MA 02139, USA.
PMID: 25155387 DOI: 10.1016/j.bmcl.2014.08.002
Abstract

Structural homology between Thrombin inhibitors and the early tetrapeptide HCV Protease Inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic β-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in biochemical and cell based assays of this novel series and confirmed by the co-crystal structure of the inhibitor with the NS3/4A protein (PDB code: 4TYD).

Keywords
HCV NS3/4A protease inhibitors; Hepatitis C; Macrocycle.