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J Med Chem ; 60(3): 1000-1017, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28075591

RESUMO

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.


Assuntos
Ciclofilinas/antagonistas & inibidores , Células Cultivadas , Cromatografia Líquida , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Ligação de Hidrogênio , Lactonas/química , Lactonas/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Termodinâmica
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