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.