Diarylpropionitrile (DPN) enantiomers: synthesis and evaluation of estrogen receptor beta-selective ligands.
Article Details
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Carroll VM, Jeyakumar M, Carlson KE, Katzenellenbogen JA
Diarylpropionitrile (DPN) enantiomers: synthesis and evaluation of estrogen receptor beta-selective ligands.
J Med Chem. 2012 Jan 12;55(1):528-37. doi: 10.1021/jm201436k. Epub 2011 Dec 14.
- PubMed ID
- 22122563 [ View in PubMed]
- Abstract
Two estrogen receptor (ER) subtypes, ERalpha and ERbeta, 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 ERalpha vs ERbeta. Some of these ligands show potential as novel therapeutic agents. Diarylpropionitrile (DPN), an ERbeta 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 ERbeta over ERalpha, 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 ERbeta 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 ERbeta function.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Estradiol Estrogen receptor alpha EC 50 (nM) 0.15 N/A N/A Details Estradiol Estrogen receptor alpha EC 50 (nM) 0.123 N/A N/A Details Estradiol Estrogen receptor alpha EC 50 (nM) 3 N/A N/A Details Estradiol Estrogen receptor alpha EC 50 (nM) 0.56 N/A N/A Details Estradiol Estrogen receptor beta EC 50 (nM) 0.4 N/A N/A Details Estradiol Estrogen receptor beta EC 50 (nM) 0.2 N/A N/A Details Estradiol Estrogen receptor beta EC 50 (nM) 1.5 N/A N/A Details Estradiol Estrogen receptor beta EC 50 (nM) 0.9 N/A N/A Details