Ciluprevir - CAS 300832-84-2
Catalog number: 300832-84-2
Category: Inhibitor
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Molecular Formula:
C40H50N6O8S
Molecular Weight:
774.93
COA:
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Targets:
HCV
Description:
Ciluprevir is used experimentally in the treatment of hepatitis C. It is manufactured by Boehringer Ingelheim Pharma GmbH & Co. kg and developed under the research code of BILN-2061. It is targeted against NS2-3 protease.
Purity:
>98%
Synonyms:
BILN 2061; BILN-2061; BILN2061; BILN-2061ZW; BILN2061ZW; BILN 2061ZW; Ciluprevir
MSDS:
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InChIKey:
PJZPDFUUXKKDNB-KNINVFKUSA-N
InChI:
InChI=1S/C40H50N6O8S/c1-23(2)41-38-43-32(22-55-38)31-19-34(28-16-15-26(52-3)17-30(28)42-31)53-27-18-33-35(47)45-40(37(49)50)20-24(40)11-7-5-4-6-8-14-29(36(48)46(33)21-27)44-39(51)54-25-12-9-10-13-25/h7,11,15-17,19,22-25,27,29,33H,4-6,8-10,12-14,18,20-21H2,1-3H3,(H,41,43)(H,44,51)(H,45,47)(H,49,50)/b11-7-/t24-,27-,29+,33+,40-/m1/s1
Canonical SMILES:
CC(C)NC1=NC(=CS1)C2=NC3=C(C=CC(=C3)OC)C(=C2)OC4CC5C(=O)NC6(CC6C=CCCCCCC(C(=O)N5C4)NC(=O)OC7CCCC7)C(=O)O
1.Mutations conferring resistance to SCH6, a novel hepatitis C virus NS3/4A protease inhibitor. Reduced RNA replication fitness and partial rescue by second-site mutations.
Yi M;Tong X;Skelton A;Chase R;Chen T;Prongay A;Bogen SL;Saksena AK;Njoroge FG;Veselenak RL;Pyles RB;Bourne N;Malcolm BA;Lemon SM J Biol Chem. 2006 Mar 24;281(12):8205-15. Epub 2005 Dec 13.
Drug resistance is a major issue in the development and use of specific antiviral therapies. Here we report the isolation and characterization of hepatitis C virus RNA replicons resistant to a novel ketoamide inhibitor of the NS3/4A protease, SCH6 (originally SCH446211). Resistant replicon RNAs were generated by G418 selection in the presence of SCH6 in a dose-dependent fashion, with the emergence of resistance reduced at higher SCH6 concentrations. Sequencing demonstrated remarkable consistency in the mutations conferring SCH6 resistance in genotype 1b replicons derived from two different strains of hepatitis C virus, A156T/A156V and R109K. R109K, a novel mutation not reported previously to cause resistance to NS3/4A inhibitors, conferred moderate resistance only to SCH6. Structural analysis indicated that this reflects unique interactions of SCH6 with P'-side residues in the protease active site. In contrast, A156T conferred high level resistance to SCH6 and a related ketoamide, SCH503034, as well as BILN 2061 and VX-950. Unlike R109K, which had minimal impact on NS3/4A enzymatic function, A156T significantly reduced NS3/4A catalytic efficiency, polyprotein processing, and replicon fitness.
2.Discovery of novel potent and selective dipeptide hepatitis C virus NS3/4A serine protease inhibitors.
Raboisson P;Lin TI;Kock Hd;Vendeville S;Vreken WV;McGowan D;Tahri A;Hu L;Lenz O;Delouvroy F;Surleraux D;Wigerinck P;Nilsson M;Rosenquist S;Samuelsson B;Simmen K Bioorg Med Chem Lett. 2008 Sep 15;18(18):5095-100. doi: 10.1016/j.bmcl.2008.07.124. Epub 2008 Aug 3.
Starting from the previously reported HCV NS3/4A protease inhibitor BILN 2061, 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 (K(i)=0.20 nM, EC(50)=3.7 nM), selective, and orally bioavailable dipeptide NS3/4A protease inhibitor, which has features attractive for further preclinical development.
3.Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients.
Kuntzen T;Timm J;Berical A;Lennon N;Berlin AM;Young SK;Lee B;Heckerman D;Carlson J;Reyor LL;Kleyman M;McMahon CM;Birch C;Schulze Zur Wiesch J;Ledlie T;Koehrsen M;Kodira C;Roberts AD;Lauer GM;Rosen HR;Bihl F;Cerny A;Spengler U;Liu Z;Kim AY;Xing Y;Schneidewind A;Madey MA;Fleckenstein JF;Park VM;Galagan JE;Nusbaum C;Walker BD;Lake-Bakaar GV;Daar ES;Jacobson IM;Gomperts ED;Edlin BR;Donfield SM;Chung RT;Talal AH;Marion T;Birren BW;Henn MR;Allen TM Hepatology. 2008 Dec;48(6):1769-78. doi: 10.1002/hep.22549.
Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-naïve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.
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CAS 300832-84-2 Ciluprevir

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