Linker Modification Enables Control of Key Functional Group Orientation in Macrocycles

Macrocycles are promising drug modalities that can enable
unique
ways of conformational preorganization, but how even minor modifications
to a macrocyclic scaffold influence the conformational preorganization
remains poorly understood. Here, we show how macrocyclization and
further derivatization of the linker region can improve affinity,
selectivity, and plasma stability in a highly atom-efficient manner.
A single, solvent-exposed methyl group was found to improve binding
affinity up to 10× over the nonmethylated analog. This led to
highly ligand-efficient macrocycles with good brain permeability,
improved solubility, and a promising in vivo profile for the FK506-binding
protein 51 (FKBP51), a key regulator of the human stress response.
Using high-resolution cocrystal structures and molecular dynamics
simulations, we found that small linker variations can be tuned to
shift the orientation of a key carbonyl group into an advantageous
position. This effect is specific to macrocycles, highlighting their
potential for fine-tuned adjustments to enable desired properties.