Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A.
J Med Chem
; 60(3): 1000-1017, 2017 02 09.
Article
em En
| MEDLINE
| ID: mdl-28075591
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ciclofilinas
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Reino Unido