RESUMO
Filarial diseases, including lymphatic filariasis and onchocerciasis, are considered among the most devastating of all tropical diseases, affecting about 145 million people worldwide. Efforts to control and eliminate onchocerciasis are impeded by a lack of effective treatments that target the adult filarial stage. Herein, we describe the discovery of a series of substituted di(pyridin-2-yl)-1,2,4-thiadiazol-5-amines as novel macrofilaricides for the treatment of human filarial infections.
Assuntos
Filariose Linfática , Oncocercose , Adulto , Aminas , HumanosRESUMO
A novel oxachrysenone series (2) of nonsteroidal selective androgen receptor modulators (SARM) was developed based on the 6-aryl-2-quinolinones (1). Synthesis and preliminary SAR results based on in vitro assays are discussed. In the cotransfection assay, lead compound 5d showed AR agonist activity more potent than dihydrotestosterone (DHT), whereas compound 17b was a potent antagonist similar to bicalutamide.
Assuntos
Androgênios , Anilidas/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Nitrilas/farmacologia , Quinolonas/química , Compostos de Tosil/farmacologia , Técnicas de Química Combinatória , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The androgen receptor is a ligand inducible transcription factor that is involved in a broad range of physiological functions. Here we describe the discovery of a new class of orally available selective androgen receptor modulators. The lead compound, 6-[(2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-4-trifluoromethylquinolin-2(1H)-one (6a), showed excellent anabolic activity in muscle with reduced effect on the prostate in a rat model of hypogonadism. The compound also improved bone strength in a rat model of post-menopausal osteoporosis.
Assuntos
Anabolizantes/síntese química , Antagonistas de Receptores de Andrógenos , Androgênios , Conservadores da Densidade Óssea/síntese química , Pirrolidinas/síntese química , Quinolinas/síntese química , Quinolonas/síntese química , Administração Oral , Anabolizantes/farmacocinética , Anabolizantes/farmacologia , Animais , Disponibilidade Biológica , Conservadores da Densidade Óssea/farmacocinética , Conservadores da Densidade Óssea/farmacologia , Feminino , Humanos , Hipogonadismo/tratamento farmacológico , Hipogonadismo/patologia , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Próstata/efeitos dos fármacos , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Quinolinas/farmacocinética , Quinolinas/farmacologia , Quinolonas/farmacocinética , Quinolonas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We previously found that oxygen-glucose-serum deprivation/restoration (OGSD/R) induces apoptosis of spinal cord astrocytes, possibly via caspase-12 and the integrated stress response, which involves protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2-alpha (eIF2α) and activating transcription factor 4 (ATF4). We hypothesized that edaravone, a low molecular weight, lipophilic free radical scavenger, would reduce OGSD/R-induced apoptosis of spinal cord astrocytes. To test this, we established primary cultures of rat astrocytes, and exposed them to 8 hours/6 hours of OGSD/R with or without edaravone (0.1, 1, 10, 100 µM) treatment. We found that 100 µM of edaravone significantly suppressed astrocyte apoptosis and inhibited the release of reactive oxygen species. It also inhibited the activation of caspase-12 and caspase-3, and reduced the expression of homologous CCAAT/enhancer binding protein, phosphorylated (p)-PERK, p-eIF2α, and ATF4. These results point to a new use of an established drug in the prevention of OGSD/R-mediated spinal cord astrocyte apoptosis via the integrated stress response.
RESUMO
Pot trials were conducted to study the influence of copper (Cu) on the growth and biomass of Elephant grass (EG, Pennisetum purpureum Schumach), Vetiver grass (VG, Vetiveria zizanioides) and the upland reed (UR, Phragmites australis). Cu toxicity in EG, VG and UR was positively correlated with the total and bioavailable Cu concentrations in the soil. Based on the EC50, dry weights, Cu contents, chlorophyll contents and photosynthesis rates, the Cu tolerance of the three species followed the trend EGNVGNUR. There were no significant differences in the unit calorific values among the different plants, though the total calorific values of EG were higher than those of VG and UR due to its higher biomass. The addition of KH2PO4 to the soil decreased the bioavailability of Cu and the Cu uptake by plants. EG could therefore be a good candidate for growth on Cu-contaminated soils, especially those improved by phosphate.
Assuntos
Biomassa , Cobre/toxicidade , Poaceae/crescimento & desenvolvimento , Poluentes do Solo/toxicidade , Análise de Variância , Calorimetria , Carboidratos/análise , Clorofila/metabolismo , Vetiveria/crescimento & desenvolvimento , Modelos Lineares , Pennisetum/crescimento & desenvolvimento , Fosfatos/química , Fotossíntese , Compostos de Potássio/química , Estresse FisiológicoRESUMO
Recent clinical trials with bisphosphonates and PTH have not supported the hypothesis that combination treatments with antiresorptive and anabolic agents would lead to synergistic activity. We hypothesized that combination treatment with a selective androgen receptor modulator (SARM), LGD-3303, and a bisphosphonate would be beneficial. In vitro competitive binding and transcriptional activity assays were used to characterize LGD-3303. LGD-3303 is a potent nonsteroidal androgen that shows little or no cross-reactivity with related nuclear receptors. Tissue selective activity of LGD-3303 was assessed in orchidectomized male rats orally administered LGD-3303 for 14 days. LGD-3303 increased the levator ani muscle weight above eugonadal levels but had greatly reduced activity on the prostate, never increasing the ventral prostate weight to >50% of eugonadal levels even at high doses. Ovariectomized female rats were treated with LGD-3303, alendronate, or combination treatment to study the effects on bone. DXA scans, histomorphometry, and biomechanics were performed. LGD-3303 increased muscle weight in females rats. In addition, LGD-3303 increased BMD and BMC at both cortical and cancellous bone sites. At cortical sites, the effects were caused in part by anabolic activity on the periosteal surface. At every measured site, combination treatment was as effective as either single agent and in some cases showed significant added benefit. LGD-3303 is a novel SARM with anabolic effects on muscle and cortical bone not observed with bisphosphonates. Combination therapy with LGD-3303 and alendronate had additive effects and may potentially be a useful therapy for osteoporosis and frailty.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Doenças Ósseas Metabólicas/tratamento farmacológico , Difosfonatos/uso terapêutico , Absorciometria de Fóton , Antagonistas de Androgênios/farmacologia , Animais , Fenômenos Biomecânicos/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/fisiopatologia , Difosfonatos/farmacologia , Sinergismo Farmacológico , Quimioterapia Combinada , Estrogênios/deficiência , Feminino , Fêmur/efeitos dos fármacos , Fêmur/patologia , Fêmur/fisiopatologia , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/patologia , Vértebras Lombares/fisiopatologia , Masculino , Orquiectomia , Tamanho do Órgão/efeitos dos fármacos , Osteocalcina/sangue , Ovariectomia , Pirróis/farmacologia , Pirróis/uso terapêutico , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transcrição Gênica/efeitos dos fármacosRESUMO
A series of selective androgen receptor modulators (SARMs) with a wide spectrum of receptor modulating activities was developed based on optimization of the 4-substituted 6-bisalkylamino-2-quinolinones (3). Significance of the trifluoromethyl group on the side chains and its interactions with amino acid residues within the androgen receptor (AR) ligand binding domain are discussed. A representative analog (9) was tested orally in a rodent model of hypogonadism and demonstrated desirable tissue selectivity.