Literature summary for 3.4.21.113 extracted from

Bogen, S.L.; Arasappan, A.; Bennett, F.; Chen, K.; Jao, E.; Liu, Y.T.; Lovey, R.G.; Venkatraman, S.; Pan, W.; Parekh, T.; Pike, R.E.; Ruan, S.; Liu, R.; Baroudy, B.; Agrawal, S.; Chase, R.; Ingravallo, P.; Pichardo, J.; Prongay, A.; Brisson, J.M.; Hsieh, T.Y.; Cheng, K.C.; Kemp, S.J.; Levy, O.E.; Lim-Wilby, M.; Tamura, S.Y.; Saksena, A.K.; Girijavallabhan, V.; Njoroge, F.G.
Discovery of SCH446211 (SCH6): a new ketoamide inhibitor of the HCV NS3 serine protease and HCV subgenomic RNA replication (2006), J. Med. Chem., 49, 2750-2757.

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Crystallization (Commentary)

Crystallization (Comment)	Organism
crystal structure of SCH446211 bound to NS3/NS4A. The P1 (S)-diastereomer is the active component. A reversible covalent bond is formed between the enzyme active site serine (Ser139) hydroxyl and the ketone carbonyl of the inhibitor. The resulting oxygen anion is stabilized by hydrogen bonding with His57. P3 tert-butyl glycine makes hydrophobic contact with the S3 pocket. The NH of the P3 carbamate and the carbonyl at P3 make H bonds with Ala-157. The P2 dimethyl-cyclopropyl proline adopts a bent conformation, placing the two methyl groups in close proximity to Arg-155. The cyclopropyl alanine residue at P1 fits well in the shallow hydrophobic S1 pocket. The P1' glycine moiety does not H bond with the enzyme backbone but allows the P1-P2' residues to form a C-clamp that wraps around the side chain of lysine 136 for improved overall binding	Hepacivirus C

Crystallization (Comment)

Organism

crystal structure of SCH446211 bound to NS3/NS4A. The P1 (S)-diastereomer is the active component. A reversible covalent bond is formed between the enzyme active site serine (Ser139) hydroxyl and the ketone carbonyl of the inhibitor. The resulting oxygen anion is stabilized by hydrogen bonding with His57. P3 tert-butyl glycine makes hydrophobic contact with the S3 pocket. The NH of the P3 carbamate and the carbonyl at P3 make H bonds with Ala-157. The P2 dimethyl-cyclopropyl proline adopts a bent conformation, placing the two methyl groups in close proximity to Arg-155. The cyclopropyl alanine residue at P1 fits well in the shallow hydrophobic S1 pocket. The P1' glycine moiety does not H bond with the enzyme backbone but allows the P1-P2' residues to form a C-clamp that wraps around the side chain of lysine 136 for improved overall binding

Hepacivirus C

Inhibitors

Inhibitors	Comment	Organism
1,1-dimethylethyl [1(S)-[[(1R,5S)-2(S)-[[[1-(cyclopropylmethyl)-3-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]-amino]-2-oxoethyl]amino]-2,3-dioxopropyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]carbonyl]-2,2-dimethylpropyl]carbamate	SCH446211, potent ketoamide inhibitor. Has low oral bioavailability in rats and monkeys, but its subcutaneous pharmacokinetic profile is remarkable, with high AUC and 100% bioavailability in both species	Hepacivirus C
1,1-dimethylethyl [1(S)-[[(1R,5S)-2(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]-4,4,4-trifluorobutyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]carbonyl]-2,2-dimethylpropyl]carbamate	-	Hepacivirus C
1,1-dimethylethyl [1(S)-[[(1R,5S)-2-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]pentyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo-[3.1.0]hexan-3-yl]carbonyl]-2,2-dimethylpropyl]carbamate	-	Hepacivirus C
2-methylpropyl [1(S)-cyclohexyl-2-[2(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl]-2-oxoethyl]carbamate	-	Hepacivirus C
2-methylpropyl [1(S)-[[(3aR,6aR)-4(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]amino]carbonyl]hexahydro-2,2-dimethyl-5H-furo[2,3-c]pyrrol-5-yl]carbonyl]-2,2-dimethylpropyl]carbamate	-	Hepacivirus C
2-methylpropyl [1(S)-[[(3aR,6aS)-1(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]amino]carbonyl]hexahydro-5,5-dimethylcyclopenta[c]pyrrol-2(1H)-yl]carbonyl]-2,2-dimethylpropyl]carbamate	-	Hepacivirus C
2-methylpropyl [1-cyclohexyl-2-[2-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]butyl]amino]carbonyl]-4(S)-[(1,1-dimethylethyl)thio]-1-pyrrolidinyl]-2-oxoethyl]carbamate	-	Hepacivirus C
2-methylpropyl [1-cyclohexyl-2-[3(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]butyl]amino]carbonyl]-6,10-dithia-2-azaspiro[4.5]-decan-2-yl]-2-oxoethyl]carbamate	-	Hepacivirus C
N-[(2-methylpropoxy)carbonyl]-(S)-tert-leucyl-N-[1(S)-[2-[[2-[[2-(dimethylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]-4(R)-methyl-(S)-prolinamide	-	Hepacivirus C
N-[(2-methylpropoxy)carbonyl]-(S)-tert-leucyl-n-[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]butyl]-4(R)-(1,1-dimethylethoxy)-(S)-prolinamide	-	Hepacivirus C
N-[(2-methylpropoxy)carbonyl]cyclohexylglucyl-N-[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]prolinamide	-	Hepacivirus C

Organism

Organism	UniProt	Comment	Textmining
Hepacivirus C	-	-	-

Synonyms

Synonyms	Comment	Organism
NS3 serine protease	-	Hepacivirus C

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism
0.000002	-	1,1-dimethylethyl [1(S)-[[(1R,5S)-2(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]-4,4,4-trifluorobutyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]carbonyl]-2,2-dimethylpropyl]carbamate	-	Hepacivirus C
0.0000038	-	1,1-dimethylethyl [1(S)-[[(1R,5S)-2(S)-[[[1-(cyclopropylmethyl)-3-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]-amino]-2-oxoethyl]amino]-2,3-dioxopropyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]carbonyl]-2,2-dimethylpropyl]carbamate	SCH446211	Hepacivirus C
0.00001	-	2-methylpropyl [1(S)-[[(3aR,6aR)-4(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]amino]carbonyl]hexahydro-2,2-dimethyl-5H-furo[2,3-c]pyrrol-5-yl]carbonyl]-2,2-dimethylpropyl]carbamate	-	Hepacivirus C
0.00001	-	2-methylpropyl [1(S)-cyclohexyl-2-[2(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl]-2-oxoethyl]carbamate	-	Hepacivirus C
0.00001	-	1,1-dimethylethyl [1(S)-[[(1R,5S)-2-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]pentyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo-[3.1.0]hexan-3-yl]carbonyl]-2,2-dimethylpropyl]carbamate	-	Hepacivirus C
0.000015	-	2-methylpropyl [1(S)-[[(3aR,6aS)-1(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]amino]carbonyl]hexahydro-5,5-dimethylcyclopenta[c]pyrrol-2(1H)-yl]carbonyl]-2,2-dimethylpropyl]carbamate	-	Hepacivirus C
0.000019	-	N-[(2-methylpropoxy)carbonyl]-(S)-tert-leucyl-n-[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]butyl]-4(R)-(1,1-dimethylethoxy)-(S)-prolinamide	-	Hepacivirus C
0.000028	-	2-methylpropyl [1-cyclohexyl-2-[3(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]butyl]amino]carbonyl]-6,10-dithia-2-azaspiro[4.5]-decan-2-yl]-2-oxoethyl]carbamate	-	Hepacivirus C
0.00012	-	2-methylpropyl [1-cyclohexyl-2-[2-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]butyl]amino]carbonyl]-4(S)-[(1,1-dimethylethyl)thio]-1-pyrrolidinyl]-2-oxoethyl]carbamate	-	Hepacivirus C
0.00014	-	N-[(2-methylpropoxy)carbonyl]-(S)-tert-leucyl-N-[1(S)-[2-[[2-[[2-(dimethylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]-4(R)-methyl-(S)-prolinamide	-	Hepacivirus C
0.01	-	N-[(2-methylpropoxy)carbonyl]cyclohexylglucyl-N-[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]prolinamide	-	Hepacivirus C