Diarylpropionitrile (DPN) Enantiomers: Synthesis and Evaluation of Estrogen Receptor beta-Selective Ligands

作者：Carroll Vincent M; Jeyakumar M; Carlson Kathryn E; Katzenellenbogen John A^*

来源：Journal of Medicinal Chemistry, 2012, 55(1): 528-537.

DOI：10.1021/jm201436k

Two estrogen receptor (ER) subtypes, ER alpha and ER beta, mediate. the actions of estrogens in diverse reproductive and nonreproductive target tissues. ER subtype-selective ligands, which bind to and activate. these subtypes differentially, have proved to be useful in elucidating which actions of estrogens proceed through ER alpha vs ER beta. Some of these ligands show potential as novel therapeutic. agents. Diarylpropionitrile (DPN), an ER beta selective ligand that we developed, is a chiral molecule, but it has been studied almost exclusively as the racemic mixture (rac-DPN, 1). Herein we report the development of an efficient enantioselective synthesis of the two isomers; R-DPN (3) and S-DPN (2), and we have compared the in vitro ligand binding affinities, coactivator binding affinities, recruitment potencies, and cellular transcriptional potencies of these isomers. Both enantiomers show a very high affinity and potency preference for ER beta over ER alpha, typically in the range of 80-300-fold. Although the enantioselectivity is only modest (3-4-fold), the R-enantiomer is the higher affinity and more potent isomer. While ER beta can be effectively and selectively stimulated by rac-DPN or by either R-DPN or S-DPN, R-DPN might be the preferred member of this isomeric series for biological studies of ER beta function.

• 出版日期2012-1-12