ABSTRACT
The discovery of a series of 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles, dual acting norepinephrine reuptake inhibitors (NRIs) and 5-HT(2A) receptor antagonists, is described. The synthesis and structure-activity relationship (SAR) of this novel series of compounds is also presented.
Subject(s)
Indoles/pharmacology , Neurotransmitter Uptake Inhibitors/chemical synthesis , Neurotransmitter Uptake Inhibitors/pharmacology , Norepinephrine/metabolism , Serotonin 5-HT2 Receptor Antagonists , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Biological Transport/drug effects , Cell Line , Humans , Indoles/chemical synthesis , Indoles/metabolism , Neurotransmitter Uptake Inhibitors/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Serotonin Antagonists/metabolism , Structure-Activity RelationshipABSTRACT
The syntheses of a series of 2-arylindene-1-ones as potent ligands of ERbeta and ERalpha are described. Several compounds exhibited high potency and moderate selectivity for the ERbeta receptor. X-ray and modeling studies were used to understand ligand binding orientation and observed affinity.
Subject(s)
Drug Design , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Indans/chemical synthesis , Indans/metabolism , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Crystallography, X-Ray , Genistein/metabolism , Genistein/pharmacology , Humans , Indans/chemistry , Ligands , Models, Molecular , Radioligand Assay , Structure-Activity Relationship , Substrate SpecificityABSTRACT
New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are >100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --> ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being >200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.
