Pharmacokinetics and Antiviral Activity of Phx1766, a Novel HCV Protease Inhibitor, Using An Accelerated Phase I Study Design

Hotho, Daphne M.; Bruijne, Joep de; O'Farrell, A. Marie; Boyea, Teresa; Li, Jianke; Bracken, Michele; Li, Xin; Campbell, David A.; Guler, Hans‐Peter; Weegink, Christine J.; Schinkel, Janke; Molenkamp, Richard; Rooij, Jeroen van de Wetering de; Vliet, André van; Janssen, Harry L.A.; Knegt, Robert J. de; Reesink, H. W.

doi:10.3851/imp1989

Cited by 11 publications

(2 citation statements)

References 25 publications

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“…By using dose-adaptive overlapping clinical trial design, the safety, tolerability, antiviral activity and pharmacokinetics of PHX1766 has been successfully checked in healthy volunteers and chronic hepatitis C patients. There was a mean maximal observed HCV RNA decline of 0.6 log 10 IU/ml in the first 24 hours and 1.5 log 10 IU/ml after 6 days of PHX1766 dosing [56].…”

Section: Teleprevir and Boceprevir Have Been Approved In May 2011 By mentioning

confidence: 99%

HCV Infection and NS-3 Serine Protease Inhibitors

Ashfaq¹

2013

Virol Mycol

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Infection with Hepatitis C Virus (HCV) is a major health problem affecting 270 million people worldwide and 10 million people in Pakistan. Currently, there is no vaccine available for prevention of HCV infection due to the high degree of strain variation. The current standard of care is a combination of Pegylated interferon α (PEG-INF α) with ribavirin and Boceprevir/Telaprevir. Hence, there is a need to develop new antiviral agents from different targets. HCV NS3, a nonstructural protein has serine/protease and helicase domain, and these domains are considered as important antiviral drug targets to combat HCV. In the past 15 years, major scientific advances have enabled the development of many novel serine/protease and helicase inhibitors by using in vivo as well as in vitro model systems. Most of NS3 protease inhibitors have entered in different clinical trials phases but still there is a need to improve the functionality of these inhibitory compounds. This review summarizes potent antiviral compounds against HCV NS3 protease and their activity in combination with standard therapy. In conclusion, it will be very exciting to see HCV NS3-4A serine protease/helicase inhibitors progress through clinical developments and, hopefully, provide hepatitis C patients with much needed, more effective therapies.

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Section: Teleprevir and Boceprevir Have Been Approved In May 2011 By mentioning

confidence: 99%

HCV Infection and NS-3 Serine Protease Inhibitors

Ashfaq¹

2013

Virol Mycol

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“…Currently, however, studies of analogs are underway which have produced compounds that appear to evade this resistance [66]. Others include Talabostat (PT-100), a multi-target anti-cancer drug which failed in Phase III [67] ; PHX1766, an HCV protease inhibitor that failed in accelerated Phase I trials [68] ; and Delanzomib, a proteasome inhibitor similar to Bortezomib and Ixazomib that failed in Phase I/II trials due to limited efficacy [69].…”

Section: Figure 4: Boron-containing Drugs In Clinical Trialsmentioning

confidence: 99%

Design and discovery of boronic acid drugs

Plescia

Moitessier

2020

European Journal of Medicinal Chemistry

139

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Research related to boronic acids, from synthetic development to materials to drug discovery, has skyrocketed in the past 20 years. In terms of drug discovery, the incorporation of boronic acids into medicinal chemistry endeavours has seen a steady increase in recent years. In fact, the Food and Drug Administration (FDA) and Health Canada have thus far approved five boronic acid drugs, three of which were approved in the past four years, and several others are in clinical trials. Boronic acids have several desirable properties that has led to their increased use, including potentially enhancing potency of drugs and/or improving their pharmacokinetics profile. This review explores discovery processes of boronic acid drugs. It begins with a brief scope of boron in natural products and in current drugs, followed by an investigation into the various rationalizations for boronic acid incorporation and the synthetic developments that focused on facilitating their addition into organic compounds. We hope that the knowledge we have assembled in this literature review will encourage medicinal chemists to consider the potential benefits of incorporating boronic acids into their future drug discovery endeavours. Contents 1. Introduction 2. Occurrence of boron in nature. Boron in bacteria. Boron in plants. Importance in mammalian systems3. Scope of boronic acid drugs 3.1. Approved boron-containing drugs 3.2. Boron-containing drugs under investigation 3.3. Over-the-counter boron-containing drugs and supplements 3.4. Boron-containing compounds in drug discovery 3.4.1. Anti-cancer boron-containing compounds 3.4.2. Anti-viral boron-containing compounds 3.4.3. Other anti-infective boron-containing compounds 3.4.4. Other therapeutic applications of boron-containing compounds 3.

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Direct-acting antivirals for chronic hepatitis C

Jakobsen

Nielsen

Feinberg

et al. 2017

Cochrane Database of Systematic Reviews

102

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Overall, DAAs on the market or under development do not seem to have any effects on risk of serious adverse events. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs seemed to reduce the risk of no sustained virological response. The clinical relevance of the effects of DAAs on no sustained virological response is questionable, as it is a non-validated surrogate outcome. All trials and outcome results were at high risk of bias, so our results presumably overestimate benefit and underestimate harm. The quality of the evidence was very low.

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Pharmacokinetics and Antiviral Activity of Phx1766, a Novel HCV Protease Inhibitor, Using An Accelerated Phase I Study Design

Cited by 11 publications

References 25 publications

HCV Infection and NS-3 Serine Protease Inhibitors

HCV Infection and NS-3 Serine Protease Inhibitors

Design and discovery of boronic acid drugs

Direct-acting antivirals for chronic hepatitis C

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