Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.

The discovery of BMS-605339 (35), a tripeptidicinhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potencyof carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1′ site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potencyand pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinolinering system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinolinering system proved to be optimal with respect to potencyand PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.