No abstract

The discovery of a second estrogen receptor (ER), called ERbeta, in 1996 sparked intense interest within the scientific community to discover its role in mediating estrogen action. However, despite more than 6 yr of research into the function of this receptor, its physiological role in mediating estrogen action remains unclear and controversial. We have developed a series of highly selective agonists for ERbeta and have characterized their activity in several clinically relevant rodent models of human disease. The activity of one such compound, ERB-041, is reported here. We conclude from these studies that ERbeta does not mediate the bone-sparing activity of estrogen on the rat skeleton and that it does not affect ovulation or ovariectomy-induced weight gain. In addition, these compounds are nonuterotrophic and nonmammotrophic. However, ERB-041 has a dramatic beneficial effect in the HLA-B27 transgenic rat model of inflammatory bowel disease and the Lewis rat adjuvant-induced arthritis model. Daily oral doses as low as 1 mg/kg reverse the chronic diarrhea of HLA-B27 transgenic rats and dramatically improve histological disease scores in the colon. The same dosing regimen in the therapeutic adjuvant-induced arthritis model reduces joint scores from 12 (maximal inflammation) to 1 over a period of 10 d. Synovitis and Mankin (articular cartilage) histological scores are also significantly lowered (50-75%). These data suggest that one function of ERbeta may be to modulate the immune response, and that ERbeta-selective ligands may be therapeutically useful agents to treat chronic intestinal and joint inflammation.

Following several recent reports that suggest that dual cAMP and cGMP phosphodiesterase 10A (PDE10A) inhibitors may present a novel mechanism to treat positive symptoms of schizophrenia, we sought to extend the preclinical characterization of two such compounds, papaverine [1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline] and MP-10 [2-{[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy]methyl}quino-line], in a variety of in vivo and in vitro assays. Both of these compounds were active in a range of antipsychotic models, antagonizing apomorphine-induced climbing in mice, inhibiting conditioned avoidance responding in both rats and mice, and blocking N-methyl-D-aspartate antagonist-induced deficits in prepulse inhibition of acoustic startle response in rats, while improving baseline sensory gating in mice, all of which strengthen previously reported observations. These compounds also demonstrated activity in several assays intended to probe negative symptoms and cognitive deficits, two disease domains that are underserved by current treatments, with both compounds showing an ability to increase sociality in BALB/cJ mice in the social approach/social avoidance assay, enhance social odor recognition in mice and, in the case of papaverine, improve novel object recognition in rats. Biochemical characterization of these compounds has shown that PDE10A inhibitors modulate both the dopamine D1-direct and D2-indirect striatal pathways and regulate the phosphorylation status of a panel of glutamate receptor subunits in the striatum. It is striking that PDE10A inhibition increased the phosphorylation of the (Ϯ)-␣-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor GluR1 subunit at residue serine 845 at the cell surface. Together, our results suggest that PDE10A inhibitors alleviate both dopaminergic and glutamatergic dysfunction thought to underlie schizophrenia, which may contribute to the broad-spectrum efficacy.Phosphodiesterase 10A (PDE10A) inhibition has generated much excitement as a potential novel mechanism for the treatment of the positive symptoms of schizophrenia (Menniti et al., 2007;Siuciak, 2008 ABBREVIATIONS: PDE10A, phosphodiesterase 10A; MP-10, 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethy]-quinoline; TP-10, 2-{4-[pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline; MK-801, dizocilpine maleate; CREB, cAMP-response element-binding protein; pCREB, phospho-cAMP-response element-binding protein; DARPP-32, dopamine and cAMP-regulated phosphoprotein of 32-kDa molecular mass; pDARPP-32, phosphodopamine and cAMP-regulated phosphoprotein of 32-kDa molecular mass; PKA, protein kinase A; cGKII, cGMP-dependent kinase type II; D1, dopamine receptor subtype 1; D2, dopamine receptor subtype 2; GluR1, glutamate receptor subunit 1; pGluR1, phosphoglutamate receptor subunit 1; GluR2/3, glutamate receptor subunit 2/glutamate receptor subunit 3; pGluR2/3, phosphoglutamate receptor subunit 2/phosphoglutamate receptor subunit 3; NMDA, N-methyl-D-aspartate; NR2B, NMDA ...

We present the structure-based optimization of a series of estrogen receptor-beta (ERbeta) selective ligands. X-ray cocrystal structures of these ligands complexed to both ERalpha and ERbeta are described. We also discuss how molecular modeling was used to take advantage of subtle differences between the two binding cavities in order to optimize selectivity for ERbeta over ERalpha. Quantum chemical calculations are utilized to gain insight into the mechanism of selectivity enhancement. Despite only two relatively conservative residue substitutions in the ligand binding pocket, the most selective compounds have greater than 100-fold selectivity for ERbeta relative to ERalpha when measured using a competitive radioligand binding assay.

A variety of 2,4-dioxoquinazolineacetic acids (10, 11) were synthesized as hybrids of the known aldose reductase inhibitors alrestatin (8), ICI-105,552 (9), and ICI-128,436 (2) and evaluated for their ability to inhibit partially purified bovine lens aldose reductase (in vitro) and their effectiveness to decrease galactitol accumulation in the 4-day galactosemic rat model (in vivo). In support to SAR studies, related analogues pyrimidinediones (12), dihydroquinazolones (13), and indazolidinones (14,15) were synthesized and tested in the in vitro and in vivo assays. All prepared compounds (10-15) have shown a high level of in vitro activity (IC50 approximately 10(-6) to 4 x 10(-8) M). However, only the 2,4-quinazolinedione analogues 10 and 11, with similar N-aralkyl substitution found in 2 and 9, have exhibited good oral potency. The remaining compounds were either inactive or had only a marginal in vivo activity. The structure-activity data support the presence of a secondary hydrophobic pocket in the vicinity of the primary lipophilic region of the enzyme.