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Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle Richard L. Mackman, Victoria A. Steadman, David K. Dean, Petr Jansa, Karine G. Poullennec, Todd C. Appleby, Carol A. Austin, Caroline A Blakemore, Ruby Cai, Carina Cannizzaro, Gregory Chin, Jean-Yves Chiva, Neil Dunbar, Hans Fliri, Adrian Highton, Hon C. Hui, Mingzhe Ji, Haolun Jin, Kapil Karki, Andrew J. Keats, Linos Lazarides, Yu-Jen Lee, Albert C. Liclican, Michael Mish, Bernard Murray, Simon B. Pettit, Peter Pyun, Michael Sangi, Rex Santos, Jonathan A. Sanvoisin, Uli Schmitz, Adam Schrier, Dustin Siegel, David Sperandio, George Stepan, Yang Tian, Gregory M. Watt, Hai Yang, and Brian Edward Schultz J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b00802 • Publication Date (Web): 03 Aug 2018 Downloaded from http://pubs.acs.org on August 3, 2018
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Journal of Medicinal Chemistry
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Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle
Richard L. Mackman,*,† Victoria A. Steadman,‡ David K. Dean,‡ Petr Jansa,† Karine G. Poullennec,‡,ǁ Todd Appleby,† Carol Austin,‡ Caroline A. Blakemore,‡┴ Ruby Cai,† Carina Cannizzaro,† Gregory Chin,† Jean-Yves C. Chiva,‡ Neil A. Dunbar,‡ Hans Fliri,§ Adrian J. Highton,‡ Hon Hui,† Mingzhe Ji,† Haolun Jin,† Kapil Karki,† Andrew J. Keats,‡ Linos Lazarides,‡ Yu-Jen Lee, † Albert Liclican,†Michael Mish,† Bernard Murray,† Simon B. Pettit,‡ Peter Pyun,† Michael Sangi,† Rex Santos,† Jonathan Sanvoisin,‡ Uli Schmitz,† Adam Schrier,† Dustin Siegel,† David Sperandio,† George Stepan,† Yang Tian,† Gregory M. Watt,‡, Hai Yang,† Brian E. Schultz.†
†
Gilead Sciences Inc.5/16/2018, 333 Lakeside Drive, Foster City, CA 94404, United
States ‡
Selcia Ltd., Fyfield Business and Research Park, Fyfield Road, Ongar, Essex CM5 0GS,
United Kingdom §
Cypralis Ltd., Babraham Research Campus, Cambridge CB22 3AT, United Kingdom
*Corresponding author:
[email protected] 1 ACS Paragon Plus Environment
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Journal of Medicinal Chemistry
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, nonimmunosuppressive 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 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
