Macrocyclization as a Strategy for Kinetic Solubility Improvement: A Comparative Analysis of Matched Molecular Pairs

In recent years, rationally designed macrocycles have
emerged as
promising therapeutic modalities for challenging drug targets. Macrocycles
can improve affinity, selectivity, and pharmacokinetic (PK) parameters,
possibly via providing semirigid, preorganized scaffolds. Nevertheless,
how macrocyclization affects PK-relevant properties is still poorly
understood. To address this question, we systematically generated
and compared 15 matched molecular pairs of macrocycles and structurally
similar linear analogs. We found that macrocyclization substantially
improves kinetic solubility while not impairing the other measured
parameters. We hypothesize that this could arise from “chameleonicity,”
which was previously reported for large, natural-product-derived macrocycles.
Our results show that the improvement of kinetic solubility is an
underappreciated aspect of macrocycles that may facilitate formulation
strategies compared to linear analogs to improve bioavailability.