Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature

The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people We designed a mechanistically unbiased approach based on chemical genetics to identify chemical starting points for interfering with HCV replication. Our differentiating strategy centred on the identification of compounds functionally distinct from those acting on the traditional targets of antiviral research in this field, the NS3 protease and the NS5B RNA-dependent RNA polymerase 10 . BMS-858 formed the basis of an extensive series of chemical refinements that focused on improving antiviral potency, broadening inhibitory activity to encompass the HCV 1a genotype, and optimizing for oral bioavailability and sustained pharmacokinetic properties. After defining symmetry as an important contributor to antiviral activity 10 , a discovery that preceded the disclosure of structural information (see below), we subsequently identified BMS-79005

Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor

The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of <b>18</b> with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C–H of the CHF₂ moiety and the backbone carbonyl of Leu135 of the enzyme. Structure–activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH₃ and CF₃ analogues, respectively, providing insight into the deployment of this unique amino acid

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 (<b>35</b>), 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 <b>35</b> 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 <b>35</b> which demonstrated antiviral activity in HCV-infected patients

Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (<b>2</b>) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to <b>2</b>, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like <b>2</b>, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (<b>1</b>) from clinical trials. Structure–activity relationships (SARs) at each of the structural subsites in <b>2</b> were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (<b>29</b>)