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The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032)
The discovery of asunaprevir (1) began with the concept of engaging the small and well-defined S(1)’ pocket of the hepatitis C virus (HCV) NS3/4A protease that was explored in the context of tripeptide carboxylic acid-based inhibitors. A cyclopropyl-acyl sulfonamide moiety was found to be the optima...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7123690/ http://dx.doi.org/10.1007/7355_2018_58 |
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author | Meanwell, Nicholas A. Rajamani, Ramkumar Scola, Paul M. Sun, Li-Qiang |
author_facet | Meanwell, Nicholas A. Rajamani, Ramkumar Scola, Paul M. Sun, Li-Qiang |
author_sort | Meanwell, Nicholas A. |
collection | PubMed |
description | The discovery of asunaprevir (1) began with the concept of engaging the small and well-defined S(1)’ pocket of the hepatitis C virus (HCV) NS3/4A protease that was explored in the context of tripeptide carboxylic acid-based inhibitors. A cyclopropyl-acyl sulfonamide moiety was found to be the optimal element at the P(1)-P(1)’ interface enhancing the potency of carboxylic acid-based prototypes by 10- to >100-fold, dependent upon the specific background. Optimization for oral bioavailability identified a 1-substituted isoquinoline-based P(2)* element that conferred a significant exposure advantage in rats compared to the matched 4-substituted quinoline isomer. BMS-605339 (30) was the first cyclopropyl-acyl sulfonamide derivative advanced into clinical trials that demonstrated dose-related reductions in plasma viral RNA in HCV-infected patients. However, 30 was associated with cardiac events observed in a normal healthy volunteer (NHV) and an HCV-infected patient that led to the suspension of the development program. Using a Langendorff rabbit heart model, a limited structure-cardiac liability relationship was quickly established that led to the discovery of 1. This compound, which differs from 30 only by changes in the substitution pattern of the P(2)* isoquinoline heterocycle and the addition of a single chlorine atom to the molecular formula, gave a dose-dependent reduction in plasma viral RNA following oral administration to HCV-infected patients without the burden of the cardiac events that had been observed with 30. A small clinical trial of the combination of 1 with the HCV NS5A inhibitor daclatasvir (2) established for the first time that a chronic genotype 1 (GT-1) HCV infection could be cured by therapy with two direct-acting antiviral agents in the absence of exogenous immune-stimulating agents. Development of the combination of 1 and 2 was initially focused on Japan where the patient population is predominantly infected with GT-1b virus, culminating in marketing approval which was granted on July 4, 2014. In order to broaden therapy to include GT-1a infections, a fixed dose triple combination of 1, 2, and the allosteric NS5B inhibitor beclabuvir (3) was developed, approved by the Japanese health authorities for the treatment of HCV GT-1 infection on December 20, 2016 and marketed as Ximency(®). |
format | Online Article Text |
id | pubmed-7123690 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
record_format | MEDLINE/PubMed |
spelling | pubmed-71236902020-04-06 The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032) Meanwell, Nicholas A. Rajamani, Ramkumar Scola, Paul M. Sun, Li-Qiang HCV: The Journey from Discovery to a Cure Article The discovery of asunaprevir (1) began with the concept of engaging the small and well-defined S(1)’ pocket of the hepatitis C virus (HCV) NS3/4A protease that was explored in the context of tripeptide carboxylic acid-based inhibitors. A cyclopropyl-acyl sulfonamide moiety was found to be the optimal element at the P(1)-P(1)’ interface enhancing the potency of carboxylic acid-based prototypes by 10- to >100-fold, dependent upon the specific background. Optimization for oral bioavailability identified a 1-substituted isoquinoline-based P(2)* element that conferred a significant exposure advantage in rats compared to the matched 4-substituted quinoline isomer. BMS-605339 (30) was the first cyclopropyl-acyl sulfonamide derivative advanced into clinical trials that demonstrated dose-related reductions in plasma viral RNA in HCV-infected patients. However, 30 was associated with cardiac events observed in a normal healthy volunteer (NHV) and an HCV-infected patient that led to the suspension of the development program. Using a Langendorff rabbit heart model, a limited structure-cardiac liability relationship was quickly established that led to the discovery of 1. This compound, which differs from 30 only by changes in the substitution pattern of the P(2)* isoquinoline heterocycle and the addition of a single chlorine atom to the molecular formula, gave a dose-dependent reduction in plasma viral RNA following oral administration to HCV-infected patients without the burden of the cardiac events that had been observed with 30. A small clinical trial of the combination of 1 with the HCV NS5A inhibitor daclatasvir (2) established for the first time that a chronic genotype 1 (GT-1) HCV infection could be cured by therapy with two direct-acting antiviral agents in the absence of exogenous immune-stimulating agents. Development of the combination of 1 and 2 was initially focused on Japan where the patient population is predominantly infected with GT-1b virus, culminating in marketing approval which was granted on July 4, 2014. In order to broaden therapy to include GT-1a infections, a fixed dose triple combination of 1, 2, and the allosteric NS5B inhibitor beclabuvir (3) was developed, approved by the Japanese health authorities for the treatment of HCV GT-1 infection on December 20, 2016 and marketed as Ximency(®). 2018-07-23 /pmc/articles/PMC7123690/ http://dx.doi.org/10.1007/7355_2018_58 Text en © Springer Nature Switzerland AG 2019 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. |
spellingShingle | Article Meanwell, Nicholas A. Rajamani, Ramkumar Scola, Paul M. Sun, Li-Qiang The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032) |
title | The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032) |
title_full | The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032) |
title_fullStr | The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032) |
title_full_unstemmed | The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032) |
title_short | The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032) |
title_sort | discovery and early clinical evaluation of the hcv ns3/4a protease inhibitor asunaprevir (bms-650032) |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7123690/ http://dx.doi.org/10.1007/7355_2018_58 |
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