Lead Optimization in Discovery Drug Metabolism and Pharmacokinetics/Case Study: The Hepatitis C Virus (HCV) Protease Inhibitor SCH 503034

2016 ◽  
pp. 196-209
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug Metabolism ◽  
Protease Inhibitor ◽  
Lead Optimization ◽  
Hcv Protease

Lead Optimization in Discovery Drug Metabolism and Pharmacokinetics/Case study: The Hepatitis C Virus (HCV) Protease Inhibitor SCH 503034

2007 ◽  
Vol 1 ◽  
pp. 1177391X0700100 ◽  
Author(s):  
K.-C. Cheng ◽  
Walter A. Korfmacher ◽  
Ronald E. White ◽  
F. George Njoroge
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug Discovery ◽  
Drug Metabolism ◽  
Protease Inhibitor ◽  
Lead Optimization ◽  
Hcv Protease

Lead optimization using drug metabolism and pharmacokinetics (DMPK) parameters has become one of the primary focuses of research organizations involved in drug discovery in the last decade. Using a combination of rapid in vivo and in vitro DMPK screening procedures on a large array of compounds during the lead optimization process has resulted in development of compounds that have acceptable DMPK properties. In this review, we present a general screening paradigm that is currently being used as part of drug discovery at Schering-Plough and we describe a case study using the Hepatitis C Virus (HCV) protease inhibitor program as an example. By using the DMPK optimization tools, a potent HCV protease inhibitor, SCH 503034, was selected for development as a candidate drug.

scholarly journals Ribavirin Antagonizes the In Vitro Anti-Hepatitis C Virus Activity of 2′-C-Methylcytidine, the Active Component of Valopicitabine

2006 ◽  
Vol 50 (10) ◽  
pp. 3444-3446 ◽  
Author(s):  
Lotte Coelmont ◽  
Jan Paeshuyse ◽  
Marc P. Windisch ◽  
Erik De Clercq ◽  
Ralf Bartenschlager ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Protease Inhibitor ◽  
Nucleoside Analogue ◽  
Active Component ◽  
Pyrimidine Nucleoside ◽  
Virus Activity ◽  
Hcv Protease

ABSTRACT Ribavirin antagonizes the in vitro anti-hepatitis C virus (HCV) activity of the pyrimidine nucleoside analogue 2′-C-methylcytidine, the active component of the experimental anti-HCV drug valopicitabine. In contrast, the combination of ribavirin with either the purine nucleoside analogue 2′-C-methyladenosine or the HCV protease inhibitor VX-950 resulted in an additive antiviral activity. These findings may have implications when planning clinical studies with valopicitabine.

scholarly journals Baseline Hepatitis C Virus (HCV) NS3 Polymorphisms and Their Impact on Treatment Response in Clinical Studies of the HCV NS3 Protease Inhibitor Faldaprevir

2013 ◽  
Vol 58 (2) ◽  
pp. 698-705 ◽  
Author(s):  
Kristi L. Berger ◽  
Ibtissem Triki ◽  
Mireille Cartier ◽  
Martin Marquis ◽  
Marie-Josée Massariol ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Amino Acid ◽  
Protease Inhibitor ◽  
Clinical Studies ◽  
Phase 2 ◽  
Genotype 1A ◽  
Treatment Naïve ◽  
Hcv Protease

ABSTRACTA challenge to the treatment of chronic hepatitis C with direct-acting antivirals is the emergence of drug-resistant hepatitis C virus (HCV) variants. HCV with preexisting polymorphisms that are associated with resistance to NS3/4A protease inhibitors have been detected in patients with chronic hepatitis C. We performed a comprehensive pooled analysis from phase 1b and phase 2 clinical studies of the HCV protease inhibitor faldaprevir to assess the population frequency of baseline protease inhibitor resistance-associated NS3 polymorphisms and their impact on response to faldaprevir treatment. A total of 980 baseline NS3 sequences were obtained (543 genotype 1b and 437 genotype 1a sequences). Substitutions associated with faldaprevir resistance (at amino acid positions 155 and 168) were rare (<1% of sequences) and did not compromise treatment response: in a phase 2 study in treatment-naive patients, six patients had faldaprevir resistance-associated polymorphisms at baseline, of whom five completed faldaprevir-based treatment and all five achieved a sustained virologic response 24 weeks after the end of treatment (SVR24). Among 13 clinically relevant amino acid positions associated with HCV protease resistance, the greatest heterogeneity was seen at NS3 codons 132 and 170 in genotype 1b, and the most common baseline substitution in genotype 1a was Q80K (99/437 [23%]). The presence of the Q80K variant did not reduce response rates to faldaprevir-based treatment. Across the three phase 2 studies, there was no significant difference in SVR24 rates between patients with genotype 1a Q80K HCV and those without Q80K HCV, whether treatment experienced (17% compared to 26%;P= 0.47) or treatment naive (62% compared to 66%;P= 0.72).

Hepatitis C virus (HCV) protease variability and anti-HCV protease inhibitor resistance in HIV/HCV-coinfected patients

HIV Medicine ◽  
2011 ◽  
Vol 12 (8) ◽  
pp. 506-509 ◽  
Author(s):  
P Trimoulet ◽  
C Belzunce ◽  
M Faure ◽  
L Wittkop ◽  
S Reigadas ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Protease Inhibitor Resistance ◽  
Hcv Protease ◽  
Inhibitor Resistance
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