[Show abstract][Hide abstract] ABSTRACT: We have synthesized and evaluated a new series of acyclic P4-benzoxaborole-based HCV NS3 protease inhibitors. Structure-activity relationships were investigated, leading to the identification of compounds 5g and 17 with low nanomolar potency in the enzymatic and cell-based replicon assay. The linker-truncated compound 5j was found to exhibit improved absorption and oral bioavailability in rats, suggesting that further reduction of molecular weight and polar surface area could result in improved drug-like properties of this novel series.
[Show abstract][Hide abstract] ABSTRACT: HCV NS3/4A serine protease is essential for the replication of the HCV virus and has been a clinically validated target. A series of HCV NS3/4A protease inhibitors containing a novel acylsulfamoyl benzoxaborole moiety at the P1' region was synthesized and evaluated. The resulting P1-P3 and P2-P4 macrocyclic inhibitors exhibited sub-nanomolar potency in the enzymatic assay and low nanomolar activity in the cell-based replicon assay. The in vivo PK evaluations of selected compounds are also described.
[Show abstract][Hide abstract] ABSTRACT: We disclose here a series of P4-benzoxaborole-substituted macrocyclic HCV protease inhibitors. These inhibitors are potent against HCV NS3 protease, their anti-HCV replicon potencies are largely impacted by substitutions on benzoxaborole ring system and P2∗ groups. P2∗ 2-thiazole-isoquinoline provides best replicon potency. The in vitro SAR studies and in vivo PK evaluations of selected compounds are described herein.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: HCV virus chronically infects more than 200 million people worldwide and current treatment option has been very limited. There is urgent demand for research and development aiming for discovery of new efficacious therapeutics. The HCV NS3/4A serine protease is considered to be essential for the replication of the virus and has been a clinically validated target. We have designed new series of acyclic, P1-P3 and P2-P4 macrocyclic compounds that contain benzoxaborole (CBO) at the P1' position. The resulting inhibitors show good enzymatic and replicon activities.
[Show abstract][Hide abstract] ABSTRACT: The NS3/4A serine protease of HCV has emerged as a drugable target for management of HCV infection because it is essential for viral replication. Herein, we report the synthesis and SAR of a new series of acyclic tripeptide-containing P4 benzoxaborole inhibitors that exhibit good biochemical potency and cellular activity. Compound 25 in this disclosure showed single digital nanomolar activity in both NS3/4A protease enzyme and cellular replicon assay, especially active against replicon genotype 1a (EC 50 =8 nM).