Tyagi M, Poongavanam V, Zich S, Lindhagen M, Asproudis I, Putra OD, Yang J, Ashworth ZJR, Guadagni A, Hagemeyer LJ, Oliva A, Sjö P, Schiesser S, Kihlberg J. Journal of Medicinal Chemistry 2026 doi:10.1021/acs.jmedchem.6c00830
Summary: Macrocycles can be useful for modulating difficult-to-drug targets, but often reside in chemical space where it is challenging to obtain sufficient cell permeability and solubility data. The authors of this manuscript determined Caco-2 cell permeability, aqueous solubility and logD for four series of macrocycles and one series of linear matched molecular pairs. X-ray crystallography, NMR spectroscopy, and computational chemistry revealed unexpected permeability differences between series and matched pairs, which were explained by differences in conformational preferences that determine the formation of intramolecular interactions. The systematic design and evaluation of the compounds in this study provides a detailed mechanistic understanding of how structural alterations affect cell permeability and solubility, often by influencing intramolecular interactions which result in shifts in conformational ensembles.
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