Literature summary for 3.4.21.98 extracted from

Taylor, J.; Zipfel, S.; Ramey, K.; Vivian, R.; Schrier, A.; Karki, K.; Katana, A.; Kato, D.; Kobayashi, T.; Martinez, R.; Sangi, M.; Siegel, D.; Tran, C.; Yang, Z.; Zablocki, J.; Yang, C.; Wang, Y.; Wang, K.; Chan, K.; Barauskas, O.; Cheng, G.; Jin, D.
Discovery of the pan-genotypic hepatitis C virus NS3/4A protease inhibitor voxilaprevir (GS-9857) A component of Vosevi (2019), Bioorg. Med. Chem. Lett., 29, 2428,2436 .

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Inhibitors

Inhibitors	Comment	Organism
(1aR,5S,10R,22aR)-5-tert-butyl-9-cyclopropyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-14-methoxy-3,6-dioxo-9-propyl-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,10R,22aR)-9-(butan-2-yl)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,10S,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-14-methoxy-3,6-dioxo-9-phenoxy-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,8S,9S,10R,19E,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,21,22,22a-dodecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,8S,9S,10R,21aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1a,3,4,5,6,9,10,17b,18,18a,19,20,21,21a-tetradecahydro-1H,8H-7,10-methanodicyclopropa[13,14:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-[(cyclopropanesulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-[(cyclopropanesulfonyl)carbamoyl]-2-ethylcyclopropyl]-18,18-difluoro-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-[(cyclopropanesulfonyl)carbamoyl]-2-ethylcyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-[(cyclopropanesulfonyl)carbamoyl]-2-methylcyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-9-ethyl-18-fluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-(2,2-difluoroethyl)cyclopropyl]-18,18-difluoro-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-(2-fluoroethyl)cyclopropyl]-18,18-difluoro-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-ethenylcyclopropyl]-18,18-difluoro-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-ethenylcyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	-	Hepacivirus C
asunaprevir	-	Hepacivirus C
danoprevir	-	Hepacivirus C
faldaprevir	-	Hepacivirus C
grazoprevir	-	Hepacivirus C
IDX-320	-	Hepacivirus C
additional information	screening for NS3/4A protease inhibitors with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. The natural peptide substrates of the HCV NS3/4A protease contain a cysteine or threonine at P1, highlighting the small nature of the S1 pocket. While replacing the P1 vinyl with an ethyl on the 3-methyl pyrrolidine series improveds the predicted clearance, the larger ethyl group results in an approximate 5fold loss in both biochemical and cellular GT3 potency. Significantly improved metabolic stability can be realized by adding a fluoro or difluoro to the P1 ethyl group, but at the expense of further compromised GT3 potency. The P1 difluoromethyl substituent appears to be a viable replacement for the reactive vinyl group wherein GT3 potency is maintained and metabolic stability is improved with compound. Compound synthesis and evaluation, detailed overview	Hepacivirus C
paritaprevir	-	Hepacivirus C
simeprevir	-	Hepacivirus C
vaniprevir	-	Hepacivirus C
vedroprevir	-	Hepacivirus C
voxilaprevir	GS-9857	Hepacivirus C

Organism

Organism	UniProt	Comment	Textmining
Hepacivirus C	-	-	-

Synonyms

Synonyms	Comment	Organism
HCV NS3/4A protease	-	Hepacivirus C
NS3/4A protease	-	Hepacivirus C

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism
0.000000043	-	(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-[(cyclopropanesulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.000000053	-	(1aR,5S,8S,9S,10R,19E,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,21,22,22a-dodecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.000000063	-	(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.000000067	-	(1aR,5S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.000000081	-	(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-ethenylcyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.000000094	-	(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-ethenylcyclopropyl]-18,18-difluoro-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.0000001	-	(1aR,5S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.00000012	-	(1aR,5S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-14-methoxy-3,6-dioxo-9-propyl-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.00000013	-	(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-9-ethyl-18-fluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.000000165	-	(1aR,5S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.00000053	-	(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-[(cyclopropanesulfonyl)carbamoyl]-2-ethylcyclopropyl]-18,18-difluoro-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.000000563	-	(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-[(cyclopropanesulfonyl)carbamoyl]-2-ethylcyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.00000063	-	(1aR,5S,10R,22aR)-9-(butan-2-yl)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.000000838	-	(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-1-[(cyclopropanesulfonyl)carbamoyl]-2-methylcyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.00000087	-	(1aR,5S,10S,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-14-methoxy-3,6-dioxo-9-phenoxy-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.00000092	-	(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-(2,2-difluoroethyl)cyclopropyl]-18,18-difluoro-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.0000013	-	(1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-(2-fluoroethyl)cyclopropyl]-18,18-difluoro-14-methoxy-9-methyl-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.0000017	-	(1aR,5S,8S,9S,10R,21aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-9-ethyl-14-methoxy-3,6-dioxo-1a,3,4,5,6,9,10,17b,18,18a,19,20,21,21a-tetradecahydro-1H,8H-7,10-methanodicyclopropa[13,14:18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C
0.0000049	-	(1aR,5S,10R,22aR)-5-tert-butyl-9-cyclopropyl-N-[(1R,2R)-2-(difluoromethyl)-1-[(1-methylcyclopropane-1-sulfonyl)carbamoyl]cyclopropyl]-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide	pH and temperature not specified in the publication	Hepacivirus C