Indazole Estrogens:  Highly Selective Ligands for the Estrogen Receptor β

Abstract

The estrogen receptors, ERalpha and ERbeta, are important pharmaceutical targets. To develop ERbeta-selective ligands, we synthesized a series of nonsteroidal compounds having a phenyl-2H-indazole core with different groups at C-3. Several of these show high affinity and good ERbetaselectivity, especially those with polar and/or polarizable substituents at this site (halogen, CF(3), nitrile); the best compounds have affinities for ERbeta comparable to estradiol, with ERbetaaffinity selectivity >100. This potency and ERbeta selectivity is also seen in cell-based transcriptional assays, where several compounds showed ERbeta efficacies equivalent to that of estradiol with ERbeta potency selectivities of 100. These compounds might prove useful as selective pharmacological probes to study the biological actions of estrogens mediated through ERbeta, and they might lead to the development of useful pharmaceuticals. These findings also contribute to an evolving pharmacophore that characterizes certain nonsteroidal ligands having high ERbeta subtype affinity and potency selectivity.

Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis

“…The therapeutic potential of ERβ-selective compounds is particularly favorable because beneficial effects of ERβ activation are independent of undesired proliferative effects on breast and uterine tissue, which are principally ERα-mediated (28). Certain haloindazoles, synthetic ERβ-specific ligands based on a halogensubstituted phenyl-2H-indazole core (8), potently inhibit transcriptional activation of inflammatory response genes in microglia and astrocytes (7). Our study demonstrates that the haloindazole Ind-Cl ameliorates chronic EAE even when treatment is initiated at peak clinical disease.…”

“…Ind-Cl [synthesized by J.A.K. 's laboratories (8)] was dissolved in 10% ethanol + 90% (vol/vol) Miglyol 812N (vehicle; Sasol) and administered s.c. daily at 5 mg/kg body weight. Control groups received (s.c.) either 0.04 mg/kg/d 17β-estradiol (E2) or 8 mg/kg/48 h DPN (4,10).…”

“…The structurally unique ERβ ligand indazole chloride (Ind-Cl), based on a halogen-substituted phenyl-2H-indazole core, is a preclinical development candidate with a strong dossier, including in vitro pharmacology using rodent and human cells, selectivity and potency data, promising absorption-distribution-metabolismexcretion findings, and pharmacokinetic profiling that includes confirmation of brain penetrability (mouse brain/plasma: ∼1.0) (7,8). It is a highly ERβ-selective (>100-fold) small molecule agonist that is administered s.c. and can be developed for oral administration (7).…”

3D-QSAR and pharmacophore model study on aryl diphenolic azoles as estrogen receptor-β ligands

“…To date, there are two subtypes of estrogen receptors encoded by different genes: estrogen receptor-a (ERa) and estrogen receptor-b (ERb) (Greene et al, 1986;Mosselman et al, 1996). Both ERs have modest overall sequence identity, differing primarily in their N-terminus domains, with the sequences more conserved at the DNA (95 % identity) and ligand-binding domains (LBD) (58 % identity) (Angelis et al, 2005). Only two amino acids are different in binding pockets of ligand complexes with ERa and ERb: Leu384 in ERa is replaced by Met336 in ERb, and Met421 in ERa is replaced by Ile373 in ERb Angelis et al, 2005;Taha et al, 2010).…”

“…Both ERs have modest overall sequence identity, differing primarily in their N-terminus domains, with the sequences more conserved at the DNA (95 % identity) and ligand-binding domains (LBD) (58 % identity) (Angelis et al, 2005). Only two amino acids are different in binding pockets of ligand complexes with ERa and ERb: Leu384 in ERa is replaced by Met336 in ERb, and Met421 in ERa is replaced by Ile373 in ERb Angelis et al, 2005;Taha et al, 2010). These two ER subtypes have different tissue distribution patterns and perform different biological functions (Kong et al, 2003;Denger et al, 2001;Vu et al, 2007).…”