Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A

  • J Med Chem. 2017 Feb 9;60(3):1000-1017. doi: 10.1021/acs.jmedchem.6b01329.
Victoria A Steadman  1 ,  Simon B Pettit  1 ,  Karine G Poullennec  1 ,  Linos Lazarides  1 ,  Andrew J Keats  1 ,  David K Dean  1 ,  Steven J Stanway  1 ,  Carol A Austin  1 ,  Jonathan A Sanvoisin  1 ,  Gregory M Watt  1 ,  Hans G Fliri  2 ,  Albert C Liclican  3 ,  Debi Jin  3 ,  Melanie H Wong  3 ,  Stephanie A Leavitt  3 ,  Yu-Jen Lee  3 ,  Yang Tian  3 ,  Christian R Frey  3 ,  Todd C Appleby  3 ,  Uli Schmitz  3 ,  Petr Jansa  3 ,  Richard L Mackman  3 ,  Brian E Schultz  3
Affiliations
  • 1. Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom.
  • 2. Cypralis Ltd. , Babraham Research Campus, Cambridge CB22 3AT, United Kingdom.
  • 3. Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
PMID: 28075591 DOI: 10.1021/acs.jmedchem.6b01329
Abstract

Cyclophilin inhibition has been a target for the treatment of hepatitis C and Other Diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic Cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18-C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a π-stacking interaction with Arg55 of Cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold to generate new lead compounds in the search for orally bioavailable Cyclophilin inhibitors.