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Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 197 Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors Targeting Different Genotypes and Drug-Resistant Variants ANNA KARIN BELFRAGE ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-554-9166-6 UPPSALA urn:nbn:se:uu:diva-243317 2015 Dissertation presented at Uppsala University to be publicly examined in B41 BMC, Husargatan 3, Uppsala, Friday, 27 March 2015 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in Swedish. Faculty examiner: Ulf Ellervik (Lunds tekniska högskola). Abstract Belfrage, A. K. 2015. Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors. Targeting Different Genotypes and Drug-Resistant Variants. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 197. 108 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9166-6. Since the first approved hepatitis C virus (HCV) NS3 protease inhibitors in 2011, numerous direct acting antivirals (DAAs) have reached late stages of clinical trials. Today, several combination therapies, based on different DAAs, with or without the need of pegylated interferon-α injection, are available for chronic HCV infections. The chemical foundation of the approved and late-stage HCV NS3 protease inhibitors is markedly similar. This could partly explain the cross-resistance that have emerged under the pressure of NS3 protease inhibitors. The first-generation NS3 protease inhibitors were developed to efficiently inhibit genotype 1 of the virus and were less potent against other genotypes. The main focus in this thesis was to design and synthesize a new class of 2(1H)-pyrazinone based HCV NS3 protease inhibitors, structurally dissimilar to the inhibitors evaluated in clinical trials or approved, potentially with a unique resistance profile and with a broad genotypic coverage. -
Genotype 3-Hepatitis C Virus' Last Line of Defense
ISSN 1007-9327 (print) ISSN 2219-2840 (online) World Journal of Gastroenterology World J Gastroenterol 2021 March 21; 27(11): 990-1116 Published by Baishideng Publishing Group Inc World Journal of W J G Gastroenterology Contents Weekly Volume 27 Number 11 March 21, 2021 FRONTIER 990 Chronic renal dysfunction in cirrhosis: A new frontier in hepatology Kumar R, Priyadarshi RN, Anand U REVIEW 1006 Genotype 3-hepatitis C virus’ last line of defense Zarębska-Michaluk D 1022 How to manage inflammatory bowel disease during the COVID-19 pandemic: A guide for the practicing clinician Chebli JMF, Queiroz NSF, Damião AOMC, Chebli LA, Costa MHM, Parra RS ORIGINAL ARTICLE Retrospective Study 1043 Efficacy and safety of endoscopic submucosal dissection for gastric tube cancer: A multicenter retrospective study Satomi T, Kawano S, Inaba T, Nakagawa M, Mouri H, Yoshioka M, Tanaka S, Toyokawa T, Kobayashi S, Tanaka T, Kanzaki H, Iwamuro M, Kawahara Y, Okada H 1055 Study on the characteristics of intestinal motility of constipation in patients with Parkinson's disease Zhang M, Yang S, Li XC, Zhu HM, Peng D, Li BY, Jia TX, Tian C Observational Study 1064 Apolipoprotein E polymorphism influences orthotopic liver transplantation outcomes in patients with hepatitis C virus-induced liver cirrhosis Nascimento JCR, Pereira LC, Rêgo JMC, Dias RP, Silva PGB, Sobrinho SAC, Coelho GR, Brasil IRC, Oliveira-Filho EF, Owen JS, Toniutto P, Oriá RB 1076 Fatigue in patients with inflammatory bowel disease in Eastern China Gong SS, Fan YH, Lv B, Zhang MQ, Xu Y, Zhao J Clinical -
Research Ethics
Q1 Performance In Initiating 2018 2019 Research Ethics Integrated Date of First Date Site Non- Reasons for Committee Research First Participant Date Site Date Site Date Site Date Site Ready To Name of Trial Participant HRA Approval Date Confirmed By Confirmation Reasons for Delay Comments delay correspond Reference Application System Recruited? Invited Selected Confirmed Start Recruited Sponsor Status to: Number Number E - Staff MEOF-002 - Methoxyflurane AnalGesia for Paediatric availability issues 70 Day Target Date Not Met. Contracting and Site 17/SC/0039 220282 Yes 10/01/2018 28/07/2017 28/07/2017 18/04/2017 05/09/2017 12/09/2017 Please Select... 25/10/2017 Both InjuriEs (MAGPIE) Staffing Delays H - Contracting delays 70 Day Target Date Not Met. Draft CTA received D - Sponsor Delays 23.10.2017; Sponsor took CTA with them from the SIV on 31.10.2017. Fully executed CTA was still Metronidazole Versus lactic acId for Treating bacterial 17/LO/1245 208149 Yes 29/11/2017 20/09/2017 20/09/2017 12/09/2017 30/10/2017 09/11/2017 Please Select... 13/11/2017 awaited on 13.11.2017, when C&C was issued. Sponsor vAginosis–VITA Green light received from Sponsor on 17.11.2017. F - No patients Study difficult to recruit to because only c.8.5% of seen potential participants are eligible. 17/LO/1363 226980 Safety and Efficacy of Two TAVI Systems Yes 29/11/2017 24/10/2017 24/10/2017 31/10/2017 18/09/2017 27/10/2017 Please Select... 23/11/2017 J - Other 70 Day Target Date Met Neither Sponsor and site agreed that the study would CTLA4 Ig (Abatacept) for prevention of abnormal start in Jan 2018 due to the potential participant.'s 14/SW/1061 131169 glucose tolerance and diabetes in relatives at risk for No 22/09/2017 22/09/2017 13/11/2017 18/09/2017 05/12/2017 Please Select.. -
Bristol-Myers Setback Another Blow to Hep C Field
August 24, 2012 Bristol-Myers setback another blow to hep C field Joanne Fagg The once-crowded field of candidates jostling to be part of the first all-oral hepatitis C antiviral cocktail got decidedly emptier today with the news that Bristol-Myers Squibb had cancelled development of its $2bn asset BMS-986094. The safety worries that had triggered a clinical hold on the drug turned out too deep to accept – a death in the original heart failure patient, plus nine other hospitalised subjects resulting from heart and kidney toxicity. Excitement around the space has already dissipated with Gilead Sciences’ seemingly uninterrupted march towards the all-oral holy grail and signs that the untreated population might be smaller than was originally believed. Failure of a closely watched candidate – and indeed one validated by a big pharma deal – will do nothing to reinvigorate the interest of investors whose interest may be turning elsewhere. Hefty price tag The news is not necessarily a setback for the nucleoside NS5B polymerase inhibitor class or for Bristol-Myers, which still has a decent pipeline in spite of some failures (see tables). However, it is another knock to sentiment for developers in the hep C space – at least, the ones that are not called Gilead (Signs are growing that the hep C ship is sailing, August 1, 2012). Hepatitis C nucleoside NS5B polymerase inhibitor pipeline Status Product Company Selected trial IDs NCT01497366 NCT01542788 Phase III GS-7977 Gilead Sciences NCT01604850 NCT01641640 NCT00869661 Phase II RG7128 Gilead Sciences/Roche NCT01057667 NCT01278134 IDX184 Idenix Pharmaceuticals Partial clinical hold Phase I RO5303253 Roche NCT01181024 NCT01371162 RO5428029 Roche NCT01345942 ALS-2200 Vertex Pharmaceuticals NCT01590407 ALS-2158 Vertex Pharmaceuticals NCT01554085 As if further confirmation were needed, California-based Gilead is now decisively in the lead to get a much- heralded all-oral hepatitis C combination to the market and address those patients thought to be awaiting a therapy free of interferon and its side effects. -
Pessimism Infects Achillion As FDA Sustains Clinical Hold
September 30, 2013 Pessimism infects Achillion as FDA sustains clinical hold Jonathan Gardner Another disappointment for the hepatitis C project sovaprevir may have Achillion Pharmaceuticals feeling like it is starting all over again. At a time when the Connecticut-based group could be riding the bio-runup heading into the AASLD liver meeting in November, executives disclosed that the FDA would not lift the clinical hold imposed after liver enzyme elevations were detected in a drug interaction study (Another hep C safety worry buffets Achillion’s lead, July 2, 2013). Shares crashed 55% to a four-year low of $3.28 in early trading today on the news, released after Friday’s market close. Acknowledging the setback, executives signalled that they were prepared to move on, with phase II testing of alternative treatment regimens imminent; while that may be an attempt to reassure, it adds months if not years to investors’ assumptions about when Achillion will start generating a royalty stream. Just like starting over With first approval decisions for Gilead Sciences’ expected $11bn drug sofosbuvir due by December and combinations from Bristol-Myers Squibb and AbbVie making strides forward, the all-oral market looks to be well served by 2017. This year is the likely earliest point that any of Achillion’s assets could begin generating sales; in 2017, Gilead’s sofosbuvir-centred franchise is expected to yield $8.2bn in sales, according to EvaluatePharma's consensus. However, Achillion executives sought to portray the company's hep C activities as broader than sovaprevir, a protease inhibitor, highlighting the NS5A inhibitor ACH-3102, a second protease inhibitor, ACH-2684, which will report combination tests with ‘3102 next year, and a uridine-analog nucleotide, ACH-3422, which could be in the clinic next year. -
Meeting Report: 26Th International Conference on Antiviral Research Q
Antiviral Research 100 (2013) 276–285 Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral Review Meeting report: 26th International Conference on Antiviral Research q R. Anthony Vere Hodge Vere Hodge Antivirals Ltd, Old Denshott, Leigh, Reigate, Surrey, UK article info abstract Article history: The 26th International Conference on Antiviral Research (ICAR) was held in San Francisco, California from Received 2 August 2013 May 11 to 15, 2013. This article summarizes the principal invited lectures at the meeting. The opening Accepted 8 August 2013 symposium on the legacy of the late Antonín Holy´ included presentations on his pioneering work with Available online 21 August 2013 nucleotide analogs, which led to the development of several antiviral drugs including tenofovir. This drug has transformed the treatment of HIV infection and has recently become the first-line therapy for chronic Keywords: hepatitis B. The Gertrude Elion Award lecturer described the anti-HIV activities of the CCR5 inhibitor Human immunodeficiency virus cenicriviroc and the reverse transcriptase inhibitor festinavirÒ, and also reviewed the evaluation of bio- Hepatitis B degradable nanoparticles with adjuvant activity. The William Prusoff Award winner reported on the cre- Hepatitis C Herpesviruses ation of NAOMI, a computer model with 21 enzymes to predict the activity of nucleoside analogs against Antiviral therapy hepatitis C virus (HCV). Other invited lecturers discussed the development of countermeasures against severe dengue and the potential of RNA virus capping and repair enzymes as drug targets. Topics in the clinical symposium included the current status of the anti-HCV compounds sovaprevir, ACH-3102, miravirsen and ALS-2200; the evaluation of single-tablet regimens for HIV infection; and the investiga- tion of cytomegalovirus resistance to CMX001. -
HCV Eradication with Direct Acting Antivirals (Daas)?
HCV eradication with direct acting antivirals (DAAs)? Emilie Estrabaud Service d’Hépatologie et INSERM UMR1149, AP-HP Hôpital Beaujon, Paris, France. [email protected] HCV eradication with direct acting antivirals (DAAs)? HCV replication HCV genome and DAAs targets NS3 inhibitors NS5A inhibitors NS5B inhibitors Take home messages HCV viral cycle Asselah et al. Liver Int. 2015;35 S1:56-64. Direct acting antivirals 5’NTR Structural proteins Nonstructural proteins 3’NTR Metalloprotease Envelope Serine protease Glycoproteins RNA Capsid RNA helicase Cofactors Polymerase C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors Telaprevir Daclatasvir Nucs Non-Nucs Boceprevir Ledipasvir Simeprevir ABT-267 Sofosbuvir ABT-333 Faldaprevir GS-5816 VX-135 Deleobuvir Asunaprevir Direct Acting Antivirals: 2015 Asselah et al. Liver Int. 2015;35 S1:56-64. Genetic barrier for HCV direct acting antivirals High Nucleos(t)ide 1 mutation= high cost to Analog Inhibitors fitness, 2-3 additional mutations to increase fitness 2 st generation Protease Inhibitors n Non Nucleos(t)ide Analog Inhibitors : NS5 A Inhibitors 1 st generation Protease Inhibitors 1 mutation= low cost to fitness Low Halfon et al. J Hepatol 2011. Vol 55(1):192-206. HCV protease inhibitors (PI) Inhibit NS3/NS4A serine protease responsible for the processing of the polyprotein 1st generation 1st generation, 2nd wave 2nd generation Resistance low low high barrier Genotype activity 1: 1 a< 1b All except 3 all Drug drug Important Less Less interaction Drugs Boceprevir Simeprevir (Janssen) MK-5172 Telaprevir Faldaprevir (BI) ACH-2684 Paritaprevir (ABT-450)/r (AbbVie) Vedroprevir (Gilead) Vaniprevir (Merck) Sovaprevir (Achillion) Asunaprevir (BMS) NS3/NS4A structure Repositioning of helicase domain Self cleavage Lipid Bilayer Inactive Insertion of the Active carboxy-terminal tail Bartenschlager et al. -
Caracterización Molecular Del Perfil De Resistencias Del Virus De La
ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en Programa de doctorado en Medicina Departamento de Medicina Facultad de Medicina Universidad Autónoma de Barcelona TESIS DOCTORAL Caracterización molecular del perfil de resistencias del virus de la hepatitis C después del fallo terapéutico a antivirales de acción directa mediante secuenciación masiva Tesis para optar al grado de doctor de Qian Chen Directores de la Tesis Dr. Josep Quer Sivila Dra. Celia Perales Viejo Dr. Josep Gregori i Font Laboratorio de Enfermedades Hepáticas - Hepatitis Víricas Vall d’Hebron Institut de Recerca (VHIR) Barcelona, 2018 ABREVIACIONES Abreviaciones ADN: Ácido desoxirribonucleico AK: Adenosina quinasa ALT: Alanina aminotransferasa ARN: Ácido ribonucleico ASV: Asunaprevir BOC: Boceprevir CCD: Charge Coupled Device CLDN1: Claudina-1 CHC: Carcinoma hepatocelular DAA: Antiviral de acción directa DC-SIGN: Dendritic cell-specific ICAM-3 grabbing non-integrin DCV: Daclatasvir DSV: Dasabuvir -
List of Completed Clinical Studies Based on the Central Clinical Hospital of the Russian Academy of Sciences (CCH RAS)
List of completed clinical studies based on the Central Clinical Hospital of the Russian Academy of Sciences (CCH RAS) 1. Protocol IFN-K-002: “A Phase IIb, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Neutralization of the Interferon Gene Signature and the Clinical Efficacy of IFNα- Kinoid in Adult Subjects With Systemic Lupus Erythematosus” Research Sponsor: Neovacs Field of study: rheumatology Study Period: 2015 -2023 Principal Investigator: MD.Ph.D. Alikhanov B.A 2. Protocol Immune/BRT/UC-0: “A Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Multi-Center Study Designed to Evaluate the Safety, Efficacy, Pharmacokinetic and Pharmacodynamic Profile of Bertilimumab in Patients With Active Moderate to Severe Ulcerative Colitis” Research Sponsor: Immune Pharmaceuticals Field of study: gastroenterology Study Period: 2017 -2018 Principal Investigator: MD.Ph.D. Alikhanov B.A 3. Protocol LTS11210( 0/ SARIL-RA-EXTEND): “A Randomized, Double-blind, Placebo- controlled, Multicenter, Two-part, Dose Ranging and Confirmatory Study With an Operationally Seamless Design, Evaluating Efficacy and Safety of SAR153191 on Top of Methotrexate (MTX) in Patients With Active Rheumatoid Arthritis Who Are Inadequate Responders to MTX Therapy” Research Sponsor: Sanofi Field of study: rheumatology Study Period: 2010 -2020 Principal Investigator: MD.Ph.D. Alikhanov B.A 4. Protocol MLN0002-3026/3027/3030 «A Randomized, Double-Blind, Double-Dummy, Multicenter, Active-Controlled Study to Evaluate the Efficacy and Safety of Vedolizumab IV Compared to Adalimumab in Subjects With Ulcerative Colitis» Research Sponsor: Takeda 1 List of completed clinical studies based on the Central Clinical Hospital of the Russian Academy of Sciences (CCH RAS) Field of study: gastroenterology Study Period: 2016 -2020 Principal Investigator: MD.Ph.D. -
A Phase II, Open-Label Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK
Official Protocol Title: A Phase II, Open-Label Clinical Trial to Study the Efficacy and Safety of the CombinationRegimen of MK-3682 + MK-8408 in Subjects with Chronic HCV Genotype 1, 2, 3, 4, 5 or 6 Infection NCT number: NCT02759315 Document Date: 26-Oct-2017 Product: MK-3682 1 Protocol/Amendment No.: 035-04 THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE STATION, NJ, U.S.A. SPONSOR: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (hereafter referred to as the Sponsor or Merck) One Merck Drive P.O. Box 100 Whitehouse Station, New Jersey, 08889-0100, U.S.A. Protocol-specific Sponsor Contact information can be found in the Investigator Trial File Binder (or equivalent). TITLE: A Phase II, Open-Label Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-3682 + MK-8408 in Subjects with Chronic HCV Genotype 1, 2, 3, 4, 5 or 6 Infection IND NUMBER: 123,749 EudraCT NUMBER: Not Applicable MK-3682-035-04 Final Protocol 26-Oct-2017 04S4N9 Confidential Product: MK-3682 2 Protocol/Amendment No.: 035-04 TABLE OF CONTENTS SUMMARY OF CHANGES................................................................................................ 10 1.0 TRIAL SUMMARY.................................................................................................. 12 2.0 TRIAL DESIGN........................................................................................................ 13 -
A Randomized, Double-Blind, Multiple-Dose Study of the Pan-Genotypic NS5A Inhibitor Samatasvir in Patients Infected with Hepatitis C Virus Genotype 1, 2, 3 Or 4
Accepted Manuscript A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4 Bradley Vince, John M. Hill, Eric J. Lawitz, William O’Riordan, Lynn R. Webster, Daniel M. Gruener, Ricky S. Mofsen, Abel Murillo, Eileen Donovan, Jie Chen, Joseph F. McCarville, John Z. Sullivan-Bólyai, Douglas Mayers, Xiao-Jian Zhou PII: S0168-8278(14)00014-2 DOI: http://dx.doi.org/10.1016/j.jhep.2014.01.003 Reference: JHEPAT 4997 To appear in: Journal of Hepatology Received Date: 8 October 2013 Revised Date: 29 December 2013 Accepted Date: 6 January 2014 Please cite this article as: Vince, B., Hill, J.M., Lawitz, E.J., O’Riordan, W., Webster, L.R., Gruener, D.M., Mofsen, R.S., Murillo, A., Donovan, E., Chen, J., McCarville, J.F., Sullivan-Bólyai, J.Z., Mayers, D., Zhou, X-J., A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4, Journal of Hepatology (2014), doi: http://dx.doi.org/10.1016/j.jhep. 2014.01.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. -
ABT-450/R (Abbott) – GS-9451 (Gilead) • Second Generation (Pan-Genotype, High Barrier to Resistance) – MK-5172 (Merck) – ACH-2684 (Achillion)
Paris Hepatitis Conference New Therapeutic Strategies Second Generation Protease inhibitors David R Nelson MD Professor and Associate Dean Director, Clinical and Translational Science Institute University of Florida Gainesville, USA Outline • HCV protease structure and drug targeting • First generation PIs – Major step forward – Major limitations • PIs in development – Second wave – Second generation • Clinical trial data – IFN-containing PI regimens – IFN-free PI containing regimens • Timelines and treatment paradigms NS3 protease targeting active site “catalytic triad” NS4A TARGETING . Substrate- and product analogs . Tri-peptides . Serine-trap inhibitors subdomain . Ketoamides (boceprevir, telaprevir) boundary . Macrocyclic inhibitors (e.g. Simeprevir, Danoprevir, Vaniprevir, etc.) zinc-finger . NS4A inhibitors Lorenz et al., Nature 2006 Kronenberger et al., Clin Liver Dis 2008 Welsch et al. Gut in press A Major Step Forward: First Generation PIs PegIFN/RBV BOC or TVR + pegIFN/RBV 100 69-83 80 63-75 40-59 60 38-44 29-40 SVR SVR (%) 40 24-29 20 7-15 5 0 Naive[1,2] Relapsers[3,4] Partial Null Responders[3,4] Responders[3,4] 1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 3. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 4. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 3. Bronowicki JP, et al. EASL 2012. Abstract 11. Limitations of First Generation PI-Based Therapy • Efficacy – Very dependent on the IFN response – Limited to gen 1 (1b>1a) • Low genetic barrier to