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J Med Chem. 2017 Feb 9;60(3):1000-1017. doi: 10.1021/acs.jmedchem.6b01329. Epub 2017 Jan 31.

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

Author information

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.

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.

PMID:
28075591
DOI:
10.1021/acs.jmedchem.6b01329
[Indexed for MEDLINE]

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