BACKGROUND: Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein-interactions, but determinants of their cell permeability and oral bioavailability are poorly understood.1 OBJECTIVE: We aim to create an understanding of the properties that govern cell permeability, efflux and solubility of macrocycles, to incorporate our learnings into guidelines describing an orally bioavailable property space for macrocycles. METHODS: We generated an extensive dataset by measuring cell permeability (Caco-2) and efflux ratios as well as aqueous solubility, LogD and pKa values under consistent experimental conditions for &gt;200, non-peptidic, de novo-designed macrocycles from the Broad Institute’s diversity-oriented screening collection, including structurally diverse sets of stereo- and regioisomers. RESULTS: This analysis revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy minimized structures for stereo- and regioisomeric sets, combined with NMR structure verification, provided fundamental insight into how, sometimes dynamic, intramolecular interactions in the 3D conformations of macrocycles are linked to physicochemical properties and permeability. IMPACT: Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable and orally bioavailable non-peptidic macrocycles.2 1Doak, B.C., Over, B., Giordanetto, F., Kihlberg, J. Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates. Chemistry & Biology (2014). 2Over et al, Molecular determinants of cell permeability and efflux of non-peptidic de novo-designed macrocycles, submitted

How to design cell permeable non-peptidic macrocycles

251st National Meeting (2016)

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