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  • In an effort to further improve the intrinsic potency

    2022-01-17

    In an effort to further improve the intrinsic potency, we evaluated the effect of the C4-substituent of the triazole (). Replacement of the phenyl group with a cyclohexyl or with a 2-pyridyl substituent led to losses in potency. Increasing the size of the substituent to a bi-phenyl or naphthyl group was tolerated. Introduction of a -chloro group on the second aryl ring had no significant effect, however, a -methoxy group led to modest improvement in potency which was improved further by the preparation of the related dihydrobenzofuran . C-terminal acyl sulfonamides have been disclosed and further evaluated as excellent bioisosteres for the C-terminal carboxylic acids in NS3 protease inhibitors. We were delighted to observe that a similar effect was observed in the triazole series, leading to a further improvement in potency of 260-fold over the corresponding caspofungin mg (). In addition, compound demonstrated sub-micromolar potency in the replicon cell-based assay. At this point, a regioselective synthesis of 1,4-disubstituted triazoles was implemented to facilitate SAR and avoid the need for regioisomer separation. This was achieved by the copper catalyzed cycloaddition chemistry previously reported for the regiospecific synthesis of 1,4-disubstituted triazoles (see ). Further modifications were evaluated toward improving cellular activity and a variety of substituted phenyls were prepared (). Introduction of a dihydrobenzofuran improved the cellular activity 2-fold over , which was improved slightly when the corresponding acetal was introduced. Introduction of a NMe group at the para-position led again to a 2-fold increase in cellular activity while an electron withdrawing sulfone resulted in complete loss of cellular activity. Replacement of phenyl with a thiophene led to a 3-fold loss in potency. The -Cl-substituted phenyl was more potent than the corresponding isomers and . Interestingly, ,-disubstitution with Cl led to a further increase in cellular activity . The same exercise was performed employing di-Br in place of di-Cl which led to our two most potent inhibitors. Further improvement in the cellular activity was achieved by modification of the capping group from a carbamate to the corresponding urea (). Also, the introduction of a methyl-substituted cyclopropane on the acyl sulfonamide improved cellular potency over and provided an inhibitor with a promising profile for further exploration.
    Hepatitis C virus is the primary etiological agent responsible for chronic HCV infections of liver leading to liver cirrhosis and hepatocellular carcinoma. Nearly 200 million people are infected worldwide and up to 80% of them turn chronic infections. Current therapeutic regimens include α-interferon and its combinations with Ribavirin, which is effective only in 25–40% of patients for sustained response. The newly introduced pegylated interferon has reduced the frequency of injection and has a sustained response in lowering viral titers and improved histological growth. The lack of efficient methods for the treatment of chronic HCV infections requires the identification of new chemical entities. Hepatitis C virus is a family virus that encodes a polyprotein of ∼3000 amino acids from a positive strand RNA genome. This polyprotein is post translationally spliced to produce various proteins essential for viral replication. Autocatalytic cleavage at the NS2–NS3 junction followed by cleavage of NS3–NS4A, NS4A–NS4B, NS4B–NS5A and NS5A–NS5B by the NS3 protease produces functionally mature virions. The inhibition of NS3 protease would possibly impair the ability of the enzyme to process the polyprotein, thus arresting maturation of virus and inhibiting viral production. HCV NS3 protease is a serine protease which enables the lesion of a Cys-Ser bond with the assistance of the cofactor NS4A. The hydrolysis of the amide bond proceeds with the attack of Ser-139 followed by the stabilization of the tetrahedral transition state by His-57 and Asp-81. We and others have developed various novel inhibitors containing a α-ketoamide moiety as an electrophilic trap that trap Ser-139 reversibly. , (), is one of the compounds that is currently undergoing Phase III clinical trials and shown to be efficacious in humans ().