The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, 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 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 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 (29).
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http://dx.doi.org/10.1021/acs.jmedchem.6b00821 | DOI Listing |
IJID Reg
March 2025
College of Medicine, Department of Clinical Science, University of Zakho, Zakho, Iraq.
Background And Objectives: Hepatitis B virus (HBV) and hepatitis C virus (HCV) are significant global health challenges, leading to severe complications such as liver cirrhosis and hepatocellular carcinoma. Despite available vaccines and treatments, these infections persist, particularly, in regions such as Iraq. This study aimed to assess the prevalence of HBV and HCV among couples attending premarital screening programs in Zakho, Kurdistan Region of Iraq and explore the associated demographic risk factors.
View Article and Find Full Text PDFFront Cell Infect Microbiol
December 2024
Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
In the context of chronic hepatitis B virus (HBV) infection, the continuous replication of HBV within host hepatocytes is a characteristic feature. Rather than directly causing hepatocyte destruction, this replication leads to immune dysfunction and establishes a state of T-B immune tolerance. Successful clearance of the HBV virus is dependent on the close collaboration between humoral and cellular immunity.
View Article and Find Full Text PDFJHEP Rep
January 2025
Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Background & Aims: The dynamics of HBV viral load (VL) in patients with chronic hepatitis B (CHB) on nucleos(t)ide analogue (NA) treatment and its relationship with liver disease are poorly understood. We aimed to study longitudinal VL patterns and their associations with CHB clinical outcomes.
Methods: Utilising large scale, routinely collected electronic health records from six centres in England, collated by the National Institute for Health and Care Research Health Informatics Collaborative (NIHR HIC), we applied latent class mixed models to investigate VL trajectory patterns in adults receiving NA treatment.
JHEP Rep
January 2025
Hepatitis Viruses and Pathobiology of Chronic Liver Diseases - LabEx DEVweCAN, Inserm U1052, Cancer Research Centre of Lyon - Hepatology Institute of Lyon F - IHU EVEREST, University of Lyon 1, ISPB, France, CNRS UMR5286, Centre Léon, Lyon, France.
Background & Aims: Owing to unexplained interpatient variation and treatment failure in hepatocellular carcinoma (HCC), novel therapeutic approaches remain an urgent clinical need. Hepatic neurons, belonging to the autonomic nervous system (ANS), mediate liver/whole body crosstalk. Pathological innervation of the ANS has been identified in cancer, nurturing tumor stroma and conferring stronger carcinogenic properties.
View Article and Find Full Text PDFJGH Open
December 2024
Department of Hepatology, School of Digestive and Liver Diseases Institute of Post Graduate Medical Education and Research Kolkata India.
Background And Objectives: Chronic viral hepatitis is a major public health challenge. The World Health Organization (WHO) and many national programs have set goals for elimination of viral hepatitis by 2030. Screening, Linkage to care (LTC), and access to treatment are very important steps to eliminate viral hepatitis.
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