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

Autor:	Steadman VA; Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom., Pettit SB; Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom., Poullennec KG; Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom., Lazarides L; Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom., Keats AJ; Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom., Dean DK; Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom., Stanway SJ; Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom., Austin CA; Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom., Sanvoisin JA; Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom., Watt GM; Selcia Ltd. , Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom., Fliri HG; Cypralis Ltd. , Babraham Research Campus, Cambridge CB22 3AT, United Kingdom., Liclican AC; Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States., Jin D; Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States., Wong MH; Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States., Leavitt SA; Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States., Lee YJ; Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States., Tian Y; Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States., Frey CR; Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States., Appleby TC; Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States., Schmitz U; Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States., Jansa P; Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States., Mackman RL; Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States., Schultz BE; Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2017 Feb 09; Vol. 60 (3), pp. 1000-1017. Date of Electronic Publication: 2017 Jan 31.
DOI:	10.1021/acs.jmedchem.6b01329
Abstrakt:	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:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu