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
  • 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.
PMID: 30074795 DOI: 10.1021/acs.jmedchem.8b00802
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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