Conformation-Based Restrictions and Scaffold Replacements in the Design of Hepatitis C Virus Polymerase Inhibitors: Discovery of Deleobuvir (BI 207127)

Abstract

Conformational restrictions of flexible torsion angles were used to guide the identification of new chemotypes of HCV NS5B inhibitors. Sites for rigidification were based on an acquired conformational understanding of compound binding requirements and the roles of substituents in the free and bound states. Chemical bioisosteres of amide bonds were explored to improve cell-based potency. Examples are shown, including the design concept that led to the discovery of the phase III clinical candidate deleobuvir (BI 207127). The structure-based strategies employed have general utility in drug design.

HCVerso1 and 2: faldaprevir with deleobuvir (BI 207127) and ribavirin for treatment-naïve patients with chronic hepatitis C virus genotype-1b infection

“…Deleobuvir (BI 207127) is a nonnucleoside inhibitor of HCV NS5B RNA polymerase that binds reversibly to thumb-pocket I of NS5B, thereby achieving potent and specific antiviral activity 17,18. In vitro and in a Phase I study, deleobuvir was more active against GT-1b than against GT-1a 17,18.…”

“…Deleobuvir (BI 207127) is a nonnucleoside inhibitor of HCV NS5B RNA polymerase that binds reversibly to thumb-pocket I of NS5B, thereby achieving potent and specific antiviral activity 17,18. In vitro and in a Phase I study, deleobuvir was more active against GT-1b than against GT-1a 17,18. The IFN-free combination of once-daily faldaprevir plus either twice-daily or three-times daily deleobuvir, with or without ribavirin, has been investigated in Phase II clinical studies in treatment-naïve patients with chronic HCV GT-1 infection 19–21.…”

HCVerso3: An Open-Label, Phase IIb Study of Faldaprevir and Deleobuvir with Ribavirin in Hepatitis C Virus Genotype-1b-Infected Patients with Cirrhosis and Moderate Hepatic Impairment

“…Deleobuvir is a non-nucleoside inhibitor of HCV NS5B RNA polymerase, which binds reversibly to the thumb-pocket I of NS5B resulting in potent and specific antiviral activity [11, 12]. In vitro and Phase 1 clinical study data show that deleobuvir is more active against GT-1b than against GT-1a [11, 12].…”

Structure–activity relationship studies on quinoxalin-2(1H)-one derivatives containing thiazol-2-amine against hepatitis C virus leading to the discovery of BH6870

“…Several classes of inhibitors for NS5B polymerase are in late-stage clinical trials or have been recently approved. The inhibitors of NS5B polymerase include nucleoside (such as sofosbuvir [37,38] and R7128 [39,40]) and nonnucleoside polymerase inhibitors (e.g., deleobuvir [41,42], tegobuvir [43][44][45]) (Fig. 1).…”