DESIGN, SYNTHESIS, AND IN VITRO SCREENING OF MACROCYCLIC UREA-BASED HETEROCYCLIC SYSTEMS WITH UNUSUAL RING CONSTRAINTS
TL;DR
The rational design, synthesis, and comprehensive biological evaluation of a novel class of macrocyclic ureas that incorporate an unusual sp3-rich constraint are reported, providing a validated, highly translatable blueprint for successfully leveraging unusual structural constraints to discover potent, orally bioavailable macrocyclic therapeutics.
Abstract
Macrocycles are highly privileged scaffolds in contemporary drug discovery, yet their inherent structural flexibility often imposes severe entropic penalties upon target binding. We report the rational design, synthesis, and comprehensive biological evaluation of a novel class of macrocyclic ureas that incorporate an unusual sp3-rich constraint. Our scalable synthetic strategy features a highly efficient palladium-catalyzed Buchwald-Hartwig intramolecular macrocyclization to assemble the rigid backbone. Rigorous structural characterization, utilizing NOESY NMR and X-ray crystallography, unambiguously confirmed that this geometric restriction forces the molecule into a tightly puckered, internally shielded, pre-organized conformation. Our in vitro biological screening demonstrated a profound amplification in target potency compared to unconstrained flexible analogues. Systematic structure-activity relationship profiling identified a fluorinated piperidine derivative as the principal lead candidate, delivering a truly outstanding nanomolar affinity with an IC50 of 42 nM. Furthermore, physicochemical profiling revealed that this constrained framework induces favorable chameleonic behavior, perfectly balancing high aqueous solubility with exceptional passive lipid membrane permeability and extended metabolic stability. Ultimately, this multidisciplinary study provides a validated, highly translatable blueprint for successfully leveraging unusual structural constraints to discover potent, orally bioavailable macrocyclic therapeutics.