title: Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A.
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.
authors.affiliation: Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Steadman
authors.affiliation: Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom.
authors.forename: Simon B
authors.initials: SB
authors.lastname: Pettit
authors.affiliation: Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom.
authors.forename: Karine G
authors.initials: KG
authors.lastname: Poullennec
authors.affiliation: Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom.
authors.forename: Linos
authors.initials: L
authors.lastname: Lazarides
authors.affiliation: Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Keats
authors.affiliation: Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom.
authors.forename: David K
authors.initials: DK
authors.lastname: Dean
authors.affiliation: Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Stanway
authors.affiliation: Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Austin
authors.affiliation: Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Sanvoisin
authors.affiliation: Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Watt
authors.affiliation: Cypralis Ltd. , Babraham Research Campus, Cambridge CB22 3AT, United Kingdom.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Fliri
authors.affiliation: Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Liclican
authors.affiliation: Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Debi
authors.initials: D
authors.lastname: Jin
authors.affiliation: Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Melanie H
authors.initials: MH
authors.lastname: Wong
authors.affiliation: Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Leavitt
authors.affiliation: Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Frey
authors.affiliation: Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Appleby
authors.affiliation: Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Uli
authors.initials: U
authors.lastname: Schmitz
authors.affiliation: Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Petr
authors.initials: P
authors.lastname: Jansa
authors.affiliation: Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Richard L
authors.identifier: 0000-0001-8861-7205
authors.initials: RL
authors.lastname: Mackman
authors.affiliation: Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Brian E
authors.identifier: 0000-0001-9757-2547
authors.initials: BE
authors.lastname: Schultz
mesh_terms: D002478:Cells, Cultured; D002853:Chromatography, Liquid; D018360:Crystallography, X-Ray; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D006801:Humans; D006860:Hydrogen Bonding; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
chemical_list: D007783:Lactones; D013141:Spiro Compounds; C121329:sanglifehrin A; D021983:Cyclophilins