Login / Signup

Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle.

Richard L MackmanVictoria A SteadmanDavid K DeanPetr JansaKarine G PoullennecTodd ApplebyCarol AustinCaroline A BlakemoreRuby CaiCarina CannizzaroGregory ChinJean-Yves C ChivaNeil A DunbarHans FliriAdrian J HightonHon HuiMingzhe JiHaolun JinKapil KarkiAndrew J KeatsLinos LazaridesYu-Jen LeeAlbert LiclicanMichael MishBernard MurraySimon B PettitPeter PyunMichael SangiRex SantosJonathan SanvoisinUli SchmitzAdam SchrierDustin SiegelDavid SperandioGeorge StepanYang TianGregory M WattHai YangBrian E Schultz
Published in: Journal of medicinal chemistry (2018)
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.
Keyphrases
  • hepatitis c virus
  • combination therapy
  • human immunodeficiency virus
  • anti inflammatory
  • photodynamic therapy
  • small molecule
  • high throughput
  • electronic health record
  • drug induced
  • electron transfer