1. Academic Validation
  2. Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle

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

  • J Med Chem. 2018 Nov 8;61(21):9473-9499. doi: 10.1021/acs.jmedchem.8b00802.
Richard L Mackman 1 Victoria A Steadman 2 David K Dean 2 Petr Jansa 1 Karine G Poullennec 2 Todd Appleby 1 Carol Austin 2 Caroline A Blakemore 2 Ruby Cai 1 Carina Cannizzaro 1 Gregory Chin 1 Jean-Yves C Chiva 2 Neil A Dunbar 2 Hans Fliri 3 Adrian J Highton 2 Hon Hui 1 Mingzhe Ji 1 Haolun Jin 1 Kapil Karki 1 Andrew J Keats 2 Linos Lazarides 2 Yu-Jen Lee 1 Albert Liclican 1 Michael Mish 1 Bernard Murray 1 Simon B Pettit 2 Peter Pyun 1 Michael Sangi 1 Rex Santos 1 Jonathan Sanvoisin 2 Uli Schmitz 1 Adam Schrier 1 Dustin Siegel 1 David Sperandio 1 George Stepan 1 Yang Tian 1 Gregory M Watt 2 Hai Yang 1 Brian E Schultz 1
Affiliations

Affiliations

  • 1 Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States.
  • 2 Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom.
  • 3 Cypralis Ltd. , Babraham Research Campus, Cambridge CB22 3AT , United Kingdom.
Abstract

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.

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