P3-P4 ureas and reverse carbamates as potent HCV NS3 protease inhibitors: Effective transposition of the P4 hydrogen bond donor
2018
Abstract A series of
tripeptidicacylsulfonamide inhibitors of HCV
NS3protease were prepared that explored structure-activity relationships (SARs) at the P4 position, and their in vitro and in vivo properties were evaluated. Enhanced potency was observed in a series of P4 ureas; however, the PK profiles of these analogues were less than optimal. In an effort to overcome the PK shortcomings, modifications to the P3-P4 junction were made. This included a strategy in which one of the two urea N–H groups was either N -methylated or replaced with an oxygen atom. The former approach provided a series of regioisomeric N -methylated ureas while the latter gave rise to P4 reverse carbamates, both of which retained potent
NS3inhibitory properties while relying upon an alternative H-bond donor topology. Details of the SARs and PK profiles of these analogues are provided.
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