title: Structural and conformational determinants of macrocycle cell permeability.
abstract: Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 non-peptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. 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 non-peptidic macrocycles with potential for oral absorption.
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Björn
authors.identifier: 0000-0002-9185-5420
authors.initials: B
authors.lastname: Over
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden.|Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), a node at the Chemical Biology Consortium Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Pär
authors.identifier: 0000-0002-9094-2581
authors.initials: P
authors.lastname: Matsson
authors.affiliation: Respiratory, Inflammation and Autoimmunity Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Tyrchan
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden.|Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), a node at the Chemical Biology Consortium Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
authors.affiliation: Department of Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Doak
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Foley
authors.affiliation: Drug Safety and Metabolism, Safety &amp;ADME Translational Sciences, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Constanze
authors.initials: C
authors.lastname: Hilgendorf
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Johnston
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Maurice D
authors.initials: MD
authors.lastname: Lee
authors.affiliation: Respiratory, Inflammation and Autoimmunity Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: McCarren
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Muncipinto
authors.affiliation: Swedish Toxicology Sciences Research Center, Södertälje, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Norinder
authors.affiliation: Respiratory, Inflammation and Autoimmunity Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
authors.forename: Matthew W D
authors.initials: MW
authors.lastname: Perry
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Duvall
authors.affiliation: Department of Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Kihlberg
mesh_terms: D018938:Caco-2 Cells; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics*; D015394:Molecular Structure; D010539:Permeability; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D047028:Macrocyclic Compounds