1381812-94-7Relevant articles and documents
Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle
Mackman, Richard L.,Steadman, Victoria A.,Dean, David K.,Jansa, Petr,Poullennec, Karine G.,Appleby, Todd,Austin, Carol,Blakemore, Caroline A.,Cai, Ruby,Cannizzaro, Carina,Chin, Gregory,Chiva, Jean-Yves C.,Dunbar, Neil A.,Fliri, Hans,Highton, Adrian J.,Hui, Hon,Ji, Mingzhe,Jin, Haolun,Karki, Kapil,Keats, Andrew J.,Lazarides, Linos,Lee, Yu-Jen,Liclican, Albert,Mish, Michael,Murray, Bernard,Pettit, Simon B.,Pyun, Peter,Sangi, Michael,Santos, Rex,Sanvoisin, Jonathan,Schmitz, Uli,Schrier, Adam,Siegel, Dustin,Sperandio, David,Stepan, George,Tian, Yang,Watt, Gregory M.,Yang, Hai,Schultz, Brian E.
, p. 9473 - 9499 (2018/09/06)
Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition (Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.
MACROCYCLIC INHIBITORS OF FLAVIVIRIDAE VIRUSES
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Page/Page column 72, (2014/01/08)
Provided are compounds of Formula I: and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of virus infections, particularly hepatitis C infections.
MACROCYCLIC INHIBITORS OF FLAVIVIRIDAE VIRUSES
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Page/Page column 87, (2012/06/30)
Provided are compounds of Formula (I): and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections, particularly hepatitis C infections.