- Macrocyclic Inhibitors of Hepatitis C Virus
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Compounds of the formula (I): and N-oxides, salts and stereoisomers thereof wherein A is OR1, NHS(═O)pR2, NHR3, NRaRb, C(═O)NHR3 or C(═O)NRaRb wherein; R1 is hydrogen, C1-C6alkyl, C0-C3alkylenecarbocyclyl, C0-C3alkyleneheterocyclyl; R2 is C1-C6alkyl, C0-C3alkylenecarbocyclyl, C0-C3alkyleneheterocyclyl or NRaRb; R3 is C1-C6alkyl, C0-C3alkylenecarbocyclyl, C0-C3alkyleneheterocyclyl, —OC1-C6alkyl, —OC0-C3alkylenecarbocyclyl, —OC0-C3alkyleneheterocyclyl; wherein any alkyl, carbocyclyl or heterocycylyl in R1, R2 or R3 are optionally substituted p is independently 1 or 2; n is 3, 4, 5 or 6; denotes an optional double bond; Rq is H or when L is CRz, Rq can also be C1-C6alkyl; Ry and Ry′ are independently C1-C6alkyl; L is N or CRz; Rz is H or forms a double bond with the asterisked carbon; W is —CH2—, —O—, —OC(═O)NH—, —OC(═O)—, —S—, —NH—, —NRa, —NHS(═O)2—, —NHC(=0)NH— or —NHC(═O)—, —NHC(═S)NH— or a bond; R8 is an optionally substituted ring system containing 1 or 2 saturated, partially saturated or unsaturated carbo or heterocyclic rings have utility in the inhibition of NS-3 serine proteases, such as flavivirus infections.
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Page/Page column 58
(2009/02/11)
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- Discovery of novel potent and selective dipeptide hepatitis C virus NS3/4A serine protease inhibitors
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Starting from the previously reported HCV NS3/4A protease inhibitor BILN 2061 (1), we have used a fast-follower approach to identify a novel series of HCV NS3/4A protease inhibitors in which (i) the P3 amino moiety and its capping group have been truncated, (ii) a sulfonamide is introduced in the P1 cyclopropyl amino acid, (iii) the position 8 of the quinoline is substituted with a methyl or halo group, and (iv) the ring size of the macrocycle has been reduced to 14 atoms. SAR analysis performed with a limited set of compounds led to the identification of N-{17-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2,14-dioxo-3,15-diazatricyclo [13.3.0.0 [Bartenschlager, R.; Lohmann, V. J. Gen. Virol. 2000, 81, 1631; Vincent Soriano, Antonio Madejon, Eugenia Vispo, Pablo Labarga, Javier Garcia-Samaniego, Luz Martin-Carbonero, Julie Sheldon, Marcelle Bottecchia, Paula Tuma, Pablo Barreiro Expert Opin. Emerg. Drugs, 2008, 13, 1-19]]octadec-7-ene-4-carbonyl}(1-methylcyclopropyl)(1-methylcyclopropyl)sulfonamide 19l an extremely potent (Ki = 0.20 nM, EC50 = 3.7 nM), selective, and orally bioavailable dipeptide NS3/4A protease inhibitor, which has features attractive for further preclinical development.
- Raboisson, Pierre,Lin, Tse-I,Kock, Herman de,Vendeville, Sandrine,Vreken, Wim Van de,McGowan, David,Tahri, Abdellah,Hu, Lili,Lenz, Oliver,Delouvroy, Frederic,Surleraux, Dominique,Wigerinck, Piet,Nilsson, Magnus,Rosenquist, Asa,Samuelsson, Bertil,Simmen, Kenneth
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scheme or table
p. 5095 - 5100
(2009/06/18)
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- HCV NS-3 serine protease inhibitors
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HCV inhibitors, compositions comprising these compounds as active ingredient, as well as processes for preparing these compounds, of formula: wherein A is
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- HCV NS-3 serine protease inhibitors
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HCV inhibitors, compositions comprising these compounds as active ingredient, as well as processes for preparing these compounds, having the formula I wherein A is
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