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

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.