A library of small tetrahydroisoquinoline ligands, previously identified via structure- and chemistry-based hierarchical organization of library scaffolds in tree-like arrangements, has been generated as novel estrogen receptor agonistic fragments via traditional medicinal chemistry exploration. The approach described has allowed for the rapid evaluation of a structure-activity relationship of the ligands concerning estrogen receptor affinity and estrogen receptor ß subtype selectivity. The structural biological insights obtained from the fragments aid the understanding of larger analogues and constitute attractive starting points for further optimization.
Möcklinghoff, S., Otterlo, van, W. A. L., Rose, R., Fuchs, S., Zimmermann, T. J., Seoane, M. D., Waldmann, H., Ottmann, C., & Brunsveld, L. (2011). Design and evaluation of fragment-like estrogen receptor tetrahydriosoquinoline ligand from a scaffold-detection approach. Journal of Medicinal Chemistry, 54(7), 2005-2011. https://doi.org/10.1021/jm1011116