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.
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HCVerso1 and 2: faldaprevir with deleobuvir (BI 207127) and ribavirin for treatment-naïve patients with chronic hepatitis C virus genotype-1b infection.
Clin Exp Gastroenterol
November 2016
Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA.
The interferon-free combination of once-daily faldaprevir 120 mg, twice-daily deleobuvir 600 mg, and weight-based ribavirin was evaluated in two Phase III studies (HCVerso1, HCVerso2) in hepatitis C virus genotype-1b-infected, treatment-naïve patients, including those ineligible for peginterferon (HCVerso2). Patients without cirrhosis were randomized to 16 weeks (Arm 1; n=208 HCVerso1, n=213 HCVerso2) or 24 weeks (Arm 2; n=211 in both studies) of faldaprevir + deleobuvir + ribavirin. Patients with compensated cirrhosis received open-label faldaprevir + deleobuvir + ribavirin for 24 weeks (Arm 3; n=51, n=72).
View Article and Find Full Text PDFShort article: Faldaprevir, deleobuvir and ribavirin in IL28B non-CC patients with HCV genotype-1a infection included in the SOUND-C3 phase 2b study.
Eur J Gastroenterol Hepatol
August 2016
aJ.W. Goethe University Hospital, Frankfurt am Main bBoehringer Ingelheim Pharma GmbH & Co. KG, Biberach cBoehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany dThe Liver Institute at Methodist Dallas Medical Center, Dallas eCentral Texas Clinical Research, Austin, Texas fNorthwest Indiana Center for Clinical Research, Valparaiso, Indiana gScripps Clinic, La Jolla, California hBoehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA iHospital Carlos III, Madrid jHospital Universitario Valle de Hebrón and CIBERehd del Instituto Carlos III, Barcelona, Spain kUniversity Clinic for Visceral Surgery and Medicine, University of Bern, Bern, Switzerland lAustin Health, Heidelberg, Victoria, Australia.
Background: SOUND-C3 was a multicentre, open-label, phase 2b study exploring the safety and efficacy of the interferon-free combination of faldaprevir (an NS3/A4 protease inhibitor), deleobuvir (BI 207127, a non-nucleoside polymerase inhibitor) and ribavirin in treatment-naive patients with chronic hepatitis C virus (HCV) genotype-1 infection. Results in patients with HCV genotype-1b and in IL28B CC genotype patients with HCV genotype-1a have been described previously. This report describes the results in IL28B non-CC genotype patients with HCV genotype-1a.
View Article and Find Full Text PDFInterferon-free treatment of chronic hepatitis C with faldaprevir, deleobuvir and ribavirin: SOUND-C3, a Phase 2b study.
Liver Int
February 2015
J. W. Goethe University Hospital, Frankfurt am Main, Germany.
Background & Aims: The safety and efficacy of the interferon-free combination of faldaprevir (NS3/A4 protease inhibitor), deleobuvir (BI 207127, non-nucleoside polymerase inhibitor), and ribavirin in treatment-naïve patients chronically infected with HCV genotype-1 was explored.
Methods: SOUND-C3 was a multicenter, open-label Phase 2b study. Treatment-naïve patients chronically infected with HCV genotype-1a (IL28B CC genotype only; n = 12) and genotype-1b (n = 20) were assigned to 16 weeks of treatment with faldaprevir 120 mg once daily, deleobuvir 600 mg twice daily, and weight-based ribavirin.
A highly concise and convergent synthesis of HCV polymerase inhibitor Deleobuvir (BI 207127): application of a one-pot borylation-Suzuki coupling reaction.
Org Lett
September 2014
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.
A highly concise and convergent synthesis of HCV polymerase inhibitor Deleobuvir (BI 207127, 1) was achieved, featuring efficient Pd-catalyzed one-pot borylation-Suzuki coupling where TFP was identified as the unique ligand effective for these transformations.
View Article and Find Full Text PDFConformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors: discovery of deleobuvir (BI 207127).
J Med Chem
March 2014
Departments of Chemistry and Biological Sciences, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5.
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.
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