2. Academic Validation
  3. Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A

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

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.

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