- Development of a New Structural Class of Broadly Acting HCV Non-Nucleoside Inhibitors Leading to the Discovery of MK-8876
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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.
- 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.
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p. 1436 - 1448
(2017/09/19)
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- Concise Cu (I) catalyzed synthesis of substituted benzofurans via a Tandem SNAr/C-O coupling process
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A novel and convergent approach to tetrasubstituted benzofurans was developed from ortho-bromo aryl fluorides and keto-Amides via one-pot SNAr displacement and subsequent Cu(I) catalyzed C-O coupling on the ortho-bromide. The scope of this methodology was demonstrated on several similar substrates.
- Song, Zhiguo J.,Tan, Lushi,Liu, Guiquan,Ye, Honglin,Dong, Jianming
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p. 1088 - 1092
(2017/01/16)
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- Process Development of the HCV NS5B Site D Inhibitor MK-8876
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We describe the route development and multikilogram-scale synthesis of an HCV NS5B site D inhibitor, MK-8876. The key topics covered are (1) process improvement of the two main fragments; (2) optimization of the initially troublesome penultimate step, a key bis(boronic acid) (BBA)-based borylation; (3) process development of the final Suzuki-Miyaura coupling; and (4) control of the drug substance form. These efforts culminated in a 28 kg delivery of the desired active pharmaceutical ingredient.
- Williams, Michael J.,Chen, Qinghao,Codan, Lorenzo,Dermenjian, Renee K.,Dreher, Spencer,Gibson, Andrew W.,He, Xianliang,Jin, Yan,Keen, Stephen P.,Lee, Alfred Y.,Lieberman, David R.,Lin, Wei,Liu, Guiquan,McLaughlin, Mark,Reibarkh, Mikhail,Scott, Jeremy P.,Strickfuss, Sophie,Tan, Lushi,Varsolona, Richard J.,Wen, Feng
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p. 1227 - 1238
(2016/07/23)
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- Facile functionalization at the C2 position of a highly substituted benzofuran
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To expedite an SAR study of the C2 position of a highly substituted benzofuran ring system, we developed a method for the preparation of a key precursor, iodide 10. From iodide 10, a diverse set of compounds with different substituents at the C2 position were prepared efficiently.
- He, Shuwen,Li, Peng,Dai, Xing,McComas, Casey C.,Du, Chunyan,Wang, Ping,Lai, Zhong,Liu, Hong,Yin, Jingjun,Bulger, Paul G.,Dang, Qun,Xiao, Dong,Zorn, Nicolas,Peng, Xuanjia,Nargund, Ravi P.,Palani, Anandan
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p. 2212 - 2216
(2014/04/17)
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- TETRACYCLIC HETEROCYCLE COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to compounds of formula (I) that are useful 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.
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- INHIBITORS OF HEPATITIS C VIRUS NS5B POLYMERASE
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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.
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- INHIBITORS OF HEPATITIS C VIRUS NS5B POLYMERASE
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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 infection and for inhibiting HCV viral replication and /or viral production in a cell-based system.
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