A New Chemotype of Chemically Tractable Nonsteroidal Estrogens Based on a Thieno[2,3‑d]pyrimidine Core

Despite continued interest in the development of nonsteroidal estrogens and antiestrogens, there are only a few chemotypes of estrogen receptor ligands. Using targeted screening in a ligand sensing assay, we identified a phenolic thieno­[2,3-d]­pyrimidine with affinity for estrogen receptor α. An efficient three-step synthesis of the heterocyclic core and structure-guided optimization of the substituents resulted in a series of potent nonsteroidal estrogens. The chemical tractability of the thieno­[2,3-d]­pyrimidine chemotype will support the design of new estrogen receptor ligands as therapeutic hormones and antihormones.