2005
DOI: 10.1021/jm049223g
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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 poten… Show more

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Cited by 198 publications
(131 citation statements)
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References 42 publications
(78 reference statements)
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“…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.…”
Section: Discussionmentioning
confidence: 72%
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“…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.…”
Section: Discussionmentioning
confidence: 72%
“…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).…”
Section: Methodsmentioning
confidence: 99%
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“…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).…”
Section: Introductionmentioning
confidence: 99%
“…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).…”
Section: Introductionmentioning
confidence: 99%