- Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants
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A series of linear HCV NS3/4A protease inhibitors was designed by eliminating the P2-P4 macrocyclic linker in grazoprevir, which, in addition to conferring conformational flexibility, allowed structure-activity relationship (SAR) exploration of diverse quinoxalines at the P2 position. Biochemical and replicon data indicated preference for small hydrophobic groups at the 3-position of P2 quinoxaline for maintaining potency against resistant variants R155K, A156T, and D168A/V. The linear inhibitors, though generally less potent than the corresponding macrocyclic analogues, were relatively easier to synthesize and less susceptible to drug resistance. Three inhibitor cocrystal structures bound to wild-type NS3/4A protease revealed a conformation with subtle changes in the binding of P2 quinoxaline, depending on the 3-position substituent, likely impacting both inhibitor potency and resistance profile. The SAR and structural analysis highlight inhibitor features that strengthen interactions of the P2 moiety with the catalytic triad residues, providing valuable insights to improve potency against resistant variants.
- Rusere, Linah N.,Matthew, Ashley N.,Lockbaum, Gordon J.,Jahangir, Muhammad,Newton, Alicia,Petropoulos, Christos J.,Huang, Wei,Kurt Yilmaz, Nese,Schiffer, Celia A.,Ali, Akbar
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- Discovery of MK-5172, a macrocyclic hepatitis C virus NS3/4a protease inhibitor
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A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
- Harper, Steven,McCauley, John A.,Rudd, Michael T.,Ferrara, Marco,DiFilippo, Marcello,Crescenzi, Benedetta,Koch, Uwe,Petrocchi, Alessia,Holloway, M. Katharine,Butcher, John W.,Romano, Joseph J.,Bush, Kimberly J.,Gilbert, Kevin F.,McIntyre, Charles J.,Nguyen, Kevin T.,Nizi, Emanuela,Carroll, Steven S.,Ludmerer, Steven W.,Burlein, Christine,Dimuzio, Jillian M.,Graham, Donald J.,McHale, Carolyn M.,Stahlhut, Mark W.,Olsen, David B.,Monteagudo, Edith,Cianetti, Simona,Giuliano, Claudio,Pucci, Vincenzo,Trainor, Nicole,Fandozzi, Christine M.,Rowley, Michael,Coleman, Paul J.,Vacca, Joseph P.,Summa, Vincenzo,Liverton, Nigel J.
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- HEPATITIS C VIRUS NS3/4A PROTEASE INHIBITORS
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The invention provides novel classes of HCV therapeutics that are orally available, safe and effective HCV NS3/4A protease inhibitors and are less susceptible to drug resistance than existing therapeutics. The invention also relates to pharmaceutical composition of these compounds and methods of preparation and use thereof.
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Paragraph 00196; 00197; 00303
(2019/01/11)
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- Synthesis of Grazoprevir, a Potent NS3/4a Protease Inhibitor for the Treatment of Hepatitis C Virus
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An efficient synthesis of grazoprevir is reported. Starting from four readily available building blocks, grazoprevir is prepared in 51% overall yield and >99.9% purity for pharmaceutical use.
- Xu, Feng,Kim, Jungchul,Waldman, Jacob,Wang, Tao,Devine, Paul
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supporting information
p. 7261 - 7265
(2018/11/23)
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- Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants
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A substrate envelope-guided design strategy is reported for improving the resistance profile of HCV NS3/4A protease inhibitors. Analogues of 5172-mcP1P3 were designed by incorporating diverse quinoxalines at the P2 position that predominantly interact with the invariant catalytic triad of the protease. Exploration of structure-activity relationships showed that inhibitors with small hydrophobic substituents at the 3-position of P2 quinoxaline maintain better potency against drug resistant variants, likely due to reduced interactions with residues in the S2 subsite. In contrast, inhibitors with larger groups at this position were highly susceptible to mutations at Arg155, Ala156, and Asp168. Excitingly, several inhibitors exhibited exceptional potency profiles with EC50 values ≤5 nM against major drug resistant HCV variants. These findings support that inhibitors designed to interact with evolutionarily constrained regions of the protease, while avoiding interactions with residues not essential for substrate recognition, are less likely to be susceptible to drug resistance.
- Matthew, Ashley N.,Zephyr, Jacqueto,Hill, Caitlin. J.,Jahangir, Muhammad,Newton, Alicia,Petropoulos, Christos J.,Huang, Wei,Kurt-Yilmaz, Nese,Schiffer, Celia A.,Ali, Akbar
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p. 5699 - 5716
(2017/07/22)
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- Process and intermediates for preparing macrolactams
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The present invention includes compounds useful as intermediates in the preparation of macrolactams, methods for preparing the intermediates, and methods for preparing macrolactams from the intermediates. One use of the methods and intermediates described herein is in the production of macrolactam compounds able to inhibit HCV NS3 protease activity. HCV NS3 inhibitory compounds have therapeutic and research applications.
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- METHODS AND INTERMEDIATES FOR PREPARING MACROLACTAMS
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The present invention includes compounds useful as intermediates in the preparation of macrolactams, methods for preparing the intermediates, and methods for preparing macrolactams. One use of the methods and intermediates described herein is in the production of macrolactam compounds able to inhibit HCV NS3 protease activity. HCV NS3 inhibitory compounds have therapeutic and research applications.
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Page/Page column 33-34
(2015/05/05)
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- MACROCYCLIC AND BICYCLIC INHIBITORS OF HEPATITIS C VIRUS
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Compounds of formula (I):or pharmaceutically acceptable salts thereof, wherein the various substituents are defined herein, methods of using said compounds, and pharmaceutical compositions containing said compounds.
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- Inhibitors of nedd8-activating enzyme
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The invention relates to an administration unit comprising crystalline form I of {(1 S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate (I-216) hydrochloride salt and to a packaging comprising the administration unit according to the invention.
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- Development of a practical, asymmetric synthesis of the hepatitis C virus protease inhibitor MK-5172
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The development of a practical, asymmetric synthesis of the hepatitis C virus (HCV) protease inhibitor MK-5172 (1), an 18-membered macrocycle, is described.
- Kuethe, Jeffrey,Zhong, Yong-Li,Yasuda, Nobuyoshi,Beutner, Gregory,Linn, Katherine,Kim, Mary,Marcune, Benjamin,Dreher, Spencer Douglas,Humphrey, Guy,Pei, Tao
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supporting information
p. 4174 - 4177
(2013/09/12)
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- HEPATITIS C VIRUS NS3 PROTEASE INHIBITORS
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The present invention relates to macrocyclic compounds of Formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.
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Page/Page column
(2013/03/26)
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- Macrocyclic Quinoxaline Compounds as HCV NS3 Protease Inhibitors
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The present invention relates to macrocyclic a compound of formula (I) and its use as inhibitors of the hepatitis C virus (HCV) NS3 protease, and in treating or preventing HCV infections.
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Page/Page column 8
(2010/03/02)
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