Title: Diarylpropionitrile (DPN) enantiomers: synthesis and evaluation of estrogen receptor ##-selective ligands.

Abstract: Two estrogen receptor (ER) subtypes, ER## and ER##, 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## vs ER##. Some of these ligands show potential as novel therapeutic agents. Diarylpropionitrile (DPN), an ER## 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## over ER##, 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## 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## function.
(PMID: 22122563)

ChEMBL Assay Type: Functional

ChEMBL Assay Data Source: Scientific Literature

ChEMBL Target ID: 19

ChEMBL target type: Target is a single protein chain