ArticleACS medicinal chemistry letters2016
Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
Article in ACS medicinal chemistry letters, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Evaluation of interactions between the hepatitis C virus NS3/4A and sulfonamidobenzamide based molecules using molecular docking, molecular dynamics simulations and binding free energy calculations.Journal of computer-aided molecular design · 2023Article
- New Methods for the Synthesis of Spirocyclic Cephalosporin Analogues.Molecules (Basel, Switzerland) · 2021Article
- Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond.Chemical reviews · 2021Review
- Targeting HIV/HCV Coinfection Using a Machine Learning-Based Multiple Quantitative Structure-Activity Relationships (Multiple QSAR) Method.International journal of molecular sciences · 2019Article
- Current therapy for chronic hepatitis C: The role of direct-acting antivirals.Antiviral research · 2017Review
- Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.ACS medicinal chemistry letters · 2016Article
Corrections and comments
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Authors and funding
38 authors.
Funding
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Abstract
We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
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