Download MendeleyNovel Macrocyclic Hcv Ns3 Protease Inhibitors Derived from Alpha-Amino Cyclic Boronates.
Li, X., Zhang, Y., Liu, Y., Ding, C.Z., Zhou, Y., Li, Q., Plattner, J.J., Baker, S.J., Zhang, S., Kazmierski, W.M., Wright, L.L., Smith, G.K., Grimes, R.M., Crosby, R.M., Creech, K.L., Carballo, L.H., Slater, M.J., Jarvest, R.L., Thommes, P., Hubbard, J.A., Convery, M.A., Nassau, P.M., Mcdowell, W., Skarzynski, T.J., Qian, X., Fan, D., Liao, L., Ni, Z.-J., Pennicott, L.E., Zou, W., Wright, J.(2010) Bioorg Med Chem Lett 20: 5695
- PubMed: 20801653
- DOI: https://doi.org/10.1016/j.bmcl.2010.08.022
- Primary Citation of Related Structures:
2XNI - PubMed Abstract:
A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around α-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.
Organizational Affiliation:
Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
