385-01-3Relevant articles and documents
Development of a New Structural Class of Broadly Acting HCV Non-Nucleoside Inhibitors Leading to the Discovery of MK-8876
McComas, Casey C.,Palani, Anandan,Chang, Wei,Holloway, M. Katharine,Lesburg, Charles A.,Li, Peng,Liverton, Nigel,Meinke, Peter T.,Olsen, David B.,Peng, Xuanjia,Soll, Richard M.,Ummat, Ajay,Wu, Jie,Wu, Jin,Zorn, Nicolas,Ludmerer, Steven W.
, p. 1436 - 1448 (2017/09/19)
Studies directed at developing a broadly acting non-nucleoside inhibitor of HCV NS5B led to the discovery of a novel structural class of 5-aryl benzofurans that simultaneously interact with both the palm I and palm II binding regions. An initial candidate was potent in vitro against HCV GT1a and GT1b replicons, and induced multi-log reductions in HCV viral load when orally dosed to chronic GT1 infected chimpanzees. However, in vitro potency losses against clinically relevant GT1a variants prompted a further effort to develop compounds with sustained potency across a broader array of HCV genotypes and mutants. Ultimately, a biology and medicinal chemistry collaboration led to the discovery of the development candidate MK-8876. MK-8876 demonstrated a pan-genotypic potency profile and maintained potency against clinically relevant mutants. It demonstrated moderate bioavailability in rats and dogs, but showed low plasma clearance characteristics consistent with once-daily dosing. Herein we describe the efforts which led to the discovery of MK-8876, which advanced into Phase 1 monotherapy studies for evaluation and characterization as a component of an all-oral direct-acting drug regimen for the treatment of chronic HCV infection.
INHIBITORS OF HEPATITIS C VIRUS NS5B POLYMERASE
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, (2011/10/03)
Compounds of formula (I) that are used as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and /or viral production in a cell-based system. Wherein Z, R30, R40, R50 and R60 of compounds of formula (I) are herein defined as in the description.
Non-steroidal dissociated glucocorticoid agonists: Indoles as A-ring mimetics and function-regulating pharmacophores
Betageri, Raj,Gilmore, Thomas,Kuzmich, Daniel,Kirrane, Thomas M.,Bentzien, J?rg,Wiedenmayer, Dieter,Bekkali, Younes,Regan, John,Berry, Angela,Latli, Bachir,Kukulka, Alison J.,Fadra, Tazmeen N.,Nelson, Richard M.,Goldrick, Susan,Zuvela-Jelaska, Ljiljana,Souza, Don,Pelletier, Josephine,Dinallo, Roger,Panzenbeck, Mark,Torcellini, Carol,Lee, Heewon,Pack, Edward,Harcken, Christian,Nabozny, Gerald,Thomson, David S.
scheme or table, p. 6842 - 6851 (2011/12/22)
We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.
PYRAZOLE COMPOUNDS
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Page/Page column 29, (2010/04/30)
The present invention relates to wherein each symbol is as defined in the specification. The compound has a superior mineralocorticoid receptor antagonistic action and is useful as an agent for the prophylaxis or treatment of a disease or condition mediated by the mineralocorticoid receptor activation.
USE OF INTERMEDIATES ((R ) -2,2, 4-TRIMETHYL-L, 3-DIOXOLANE-4-YL) METHANOL (A), 3-F LUORO-4-NITRO-PHENOL (B) AND 1- (4-CHLORO- BENZYL) -PIPERIDIN-4-YLAMINE (C)
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Page/Page column 8; 19-20, (2009/04/25)
The present invention relates to novel processes for the preparation of intermediate compounds which can be used to prepare therapeutic agents. The present invention also relates to novel intermediate compounds which can be used to prepare therapeutic agents. More specifically, the invention relates to the use of intermediates ((R) -2,2,4-trimethyl-l, 3- dioxolane-4 -yl) methanol (A), 3-f luoro-4-nitro-phenol (B) and 1- (4-chloro-benZyl) -piperidin-4-ylamine (C).
The neighboring group effect of fluorine in the tritium labeling of organic substrates with [Cp*(PMe3)IrMe(CH2Cl 2)]+ [BArf]-, a cationic iridium(III) complex
Skaddan, Marc B.,Bergman, Robert G.
, p. 623 - 634 (2007/10/03)
The cationic Ir(III) complex, [Cp*(PMe3)IrMe(CH 2Cl2)][BArf] (1, Cp* = η5-C5Me5, BArf = MeB(C 6F5)3), has been shown to be a useful reagent in the tritium and deuterium labeling of organic substrates. During a recent reaction of 1 with a fluorinated molecule, we observed an unusually high incorporation of tritium ortho to the aromatic fluorines. To probe whether this was an isolated incident or a more general phenomenon, we have investigated the application of 1 towards the tritiation of simple fluorinated organic substrates. Our results indicate that aromatic fluorine indeed does exhibit a neighboring group effect in terms of directing ortho H/T exchange. The directing influence appears to be at least as strong as the hydroxyl moiety reported in previous works. Copyright
1,1,1-TRIFLUORO-4-PHENYL-4-METHYL-2-(1H-PYRROLO
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Page/Page column 182-183, (2010/02/11)
Compounds of Formula (IA), IB), IC), and (ID) wherein R1, R2, R3, R4, R5, and R6 are as respectively defined herein for Formula (IA), (IB), (IC), and (ID), or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.
Synthesis and characterization of two improved NMR indicators for cytosolic Ca2+: 3FBAPTA and 35FBAPTA
Levy, Louis A.,Gabel, Scott A.,London, Robert E.
, p. 440 - 446 (2007/10/03)
Fluorinated derivatives of the calcium-selective chelator BAPTA [1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid] are popular NMR probes for cytosolic calcium ion concentration. Two such derivatives were synthesized and evaluated, 3FBAPTA [1,2-bis(2-amino-3-fluorophenoxy)ethane-N,N,N′,N′-tetraacetic acid] and 35FBAPTA [1,2-bis(2-amino-3,5-difluorophenoxy)ethane-N,N,N′,N′-tetraacetic acid]. The dissociation constant ratios obtained at 37°C were K3FD/K5FD = 0.60 and K35FD/K5FD = 0.88; similar values were obtained at 25°C. Hence 3FBAPTA binds calcium ions more tightly than 5FBAPTA [1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N′,N′-tetraacetic acid, the currently most frequently utilized indicator], while the doubly substituted derivative exhibits intermediate affinity. The dissociation rate constants for the calcium complexes measured at 37°C exhibit a similar trend, with k5-1 > k35-1 > k3-1. Both of the additional derivatives exhibit slow exchange kinetics, and should be superior fluorine NMR probes owing to the decreased T1 values and, in the case of 35FBAPTA, the presence of two calcium-sensitive fluorine nuclei which are measured simultaneously.
