Discovery of Novel Urea-Based Hepatitis C Protease Inhibitors with High Potency against Protease-Inhibitor-Resistant Mutants

The macrocyclic urea <b>2</b>, a byproduct in the synthesis of benzoxaborole <b>1</b>, was identified to be a novel and potent HCV protease inhibitor. We further explored this motif by synthesizing additional urea-based inhibitors and by characterizing them in replicase HCV protease-resistant mutants assay. Several compounds, exemplified by <b>12</b>, were found to be more potent in HCV replicon assays than leading second generation inhibitors such as danoprevir and TMC-435350. Additionally, following oral administration, inhibitor <b>12</b> was found in rat liver in significantly higher concentrations than those reported for both danoprevir and TMC-435350, suggesting that inhibitor <b>12</b> has the combination of anti-HCV and pharmacokinetic properties that warrants further development of this series

Design, Structure–Activity Relationship, and in Vivo Characterization of the Development Candidate NVP-HSP990

Utilizing structure-based drug design, a novel dihydropyridopyrimidinone series which exhibited potent Hsp90 inhibition, good pharmacokinetics upon oral administration, and an excellent pharmacokinetic/pharmacodynamic relationship in vivo was developed from a commercial hit. The exploration of this series led to the selection of NVP-HSP990 as a development candidate

Synthesis and evaluation of novel a-amino cyclic boronates as inhibitors of HCV NS3 protease

We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described

Novel macrocyclic HCV NS3 protease inhibitors derived from a-amino cyclic boronates

A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with a-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 a-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