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

Abstract

The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of 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 potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.

Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor

“…A 1.2–1.8 log 10 viral load decline in HCV RNA was observed following a single 60–120 mg dose of BMS‐605339 to patients infected with HCV GT 1. This equates to an estimated total liver level of between ∼60 and 120 nM (∼ 10 × 1a viral replicon EC 50 ) . Therefore, at the time when these calculations were made, the targeted human total liver level for ASV was set to 40 nM (10 × 1a viral replicon EC 50 ), which was converted back to a targeted plasma C min (1 nM) using the most conservative liver to plasma observed in the preclinical species (40 from the dog).…”

Preclinical Pharmacokinetics and In Vitro Metabolism of BMS-605339: A Novel HCV NS3 Protease Inhibitor

“…The antiviral response was dose‐dependent with a mean 1.8 log 10 reduction in viral load observed 12 h after a single 120 mg dose. Although there was a favorable antiviral response in human subjects, clinically important electrocardiographic changes were noted and further development of this compound was discontinued . As a result of these findings, further studies with a close analog of BMS‐605339 led to the discovery of asunaprevir (BMS‐650032) .…”

“…It is a specific and selective competitive inhibitor of the HCV nonstructural (NS) 3/4A serine protease complex that is essential for HCV polyprotein processing and subsequent viral replication. BMS‐605339 exerts its antiviral activity in HCV replicon cell‐based systems representing genotypes 1a (EC 50 = 8 nM) and 1b (EC 50 = 3 nM) . Mechanistic and resistance studies suggest that BMS‐605339 specifically targets HCV NS3 proteolytic activity.…”

“…Importantly, BMS‐605339 has been demonstrated to be clinically efficacious, producing a maximum decline in HCV RNA viral titer of −1.8 log 10 IU/mL after a single 120‐mg oral (p.o.) dose in HCV‐infected patients …”

“…1) was selected from a series of molecules designed to optimize the in vitro and in vivo pharmacokinetic properties by systematically exploring variation of the substituents. 5 It is a specific and selective competitive inhibitor of the HCV nonstructural (NS) 3/4A serine protease complex that is essential for HCV polyprotein processing and subsequent viral replication. BMS-605339 exerts its antiviral activity in HCV replicon cell-based systems representing genotypes 1a (EC 50 = 8 nM) and 1b (EC 50 = 3 nM).…”