Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A
| Autor: | Yu-Jen Lee, Andrew John Keats, Karine G. Poullennec, Uli Schmitz, Todd C. Appleby, Hans G. Fliri, Linos Lazarides, Albert Liclican, Steven J. Stanway, David Kenneth Dean, Debi Jin, Victoria Alexandra Steadman, Simon B. Pettit, Stephanie A. Leavitt, Yang Tian, Jonathan Sanvoisin, Petr Jansa, Brian E. Schultz, Christian R. Frey, Melanie H. Wong, Gregory M. Watt, Richard L. Mackman, Carol Austin |
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| Rok vydání: | 2017 |
| Předmět: |
Spectrometry
Mass Electrospray Ionization Stereochemistry Proton Magnetic Resonance Spectroscopy Tripeptide Crystallography X-Ray 010402 general chemistry 01 natural sciences Chemical synthesis Stereocenter Cyclophilins Lactones Structure-Activity Relationship Residue (chemistry) chemistry.chemical_compound Cyclophilin A Drug Discovery Humans Moiety Spiro Compounds Cells Cultured Cyclophilin Natural product 010405 organic chemistry Hydrogen Bonding Surface Plasmon Resonance 0104 chemical sciences chemistry Thermodynamics Molecular Medicine Chromatography Liquid |
| Zdroj: | Journal of Medicinal Chemistry. 60:1000-1017 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b01329 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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