Toward Selective ERβ Agonists for Central Nervous System Disorders:  Synthesis and Characterization of Aryl Benzthiophenes

Abstract

In an effort to identify selective ligands for the estrogen receptor subtype ERbeta, a series of aryl benzthiophenes was synthesized. In a radioligand binding assay and reporter gene assays in HeLa and SH-SY5Y cells, compounds were characterized as ERbeta-selective agonists. By targeting ERbeta in the brain, these compounds could lead to drugs able to separate the beneficial effects of estrogens on mood, learning, and memory from side effects such as the stimulation of endometrial and breast cancer.

Palladium‐Catalyzed Selective Synthesis of Naphthalenes and Indenones and Their Luminescent Properties

“…β-Arylnaphthalene derivatives, [1] usually modeled as simplified genisteins to enhance estrogen receptor selectivity, [2] have been widely explored, and it has been demonstrated that they have unique advantages over other classes, such as biphenyls, [3] tetrahydrochrysenes, [4] arylbenzthiophenes, [5] triazines, [6] and diarylpropionitriles. [7] β-Arylnaphthalene derivatives are also useful luminescent materials [8] and smectic liquid crystalline photoconductors [9] in the study of intrinsic photocarrier generation.…”

WJD008, a Dual Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin Inhibitor, Prevents PI3K Signaling and Inhibits the Proliferation of Transformed Cells with Oncogenic PI3K Mutant

“…In this study, we chose compound 2 as our lead compound for further optimization because of its good selectivity for p110␣. It has been reported that the cyano group and thio atom have similar lipophilicity properties, and they were used as bioisosteres in estrogen receptor ligand design successfully (Meyers et al, 2001;Schopfer et al, 2002). Here, we simplified the thienopyrimidine scaffold into a 5-cyanopyrimidine ring and kept the morpholine and 3-substitutedphenyl ring that bound to the ATP binding pocket (Knight et al, 2006) of PI3K.…”

Triazolo-tetrahydrofluorenones as selective estrogen receptor beta agonists

“…3,4 The potential that subtype-selective compounds might lead to new therapies, as well as to further the understanding of estrogen biology, has lead a number of groups to pursue ERa-selective 5 and ERb-selective agents. [6][7][8][9][10][11][12][13][14][15][16] We have previously reported that compounds derived from the phenolic tetrahydrofluorenone framework (I), as exemplified by compound 1, are subtype-selective agonists of ERb. 17 While many compounds of this class performed well in vitro in receptor binding and cellbased transactivation assays, as a class they displayed poor pharmacokinetic properties characterized by rapid clearance and low oral bioavailability.…”