RESUMEN
A series of 1-(3-aryloxyaryl)benzimidazoles incorporating a sulfone substituent (6) was prepared. High affinity LXR ligands were identified (LXRbeta binding IC(50) values <10nM), some with excellent agonist potency and efficacy in a functional assay of LXR activity measuring ABCA1 mRNA increases in human macrophage THP1 cells. The compounds were typically stable in liver microsome preparations and had good oral exposure in mice.
Asunto(s)
Bencimidazoles/síntesis química , Receptores Nucleares Huérfanos/agonistas , Sulfonas/química , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Bencimidazoles/química , Bencimidazoles/farmacocinética , Línea Celular , Humanos , Receptores X del Hígado , Ratones , Microsomas Hepáticos/metabolismo , Receptores Nucleares Huérfanos/metabolismo , ARN Mensajero/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
A series of 4-(3-aryloxyaryl)quinolines with sulfone substituents on the terminal aryl ring (7) was prepared as LXR agonists. High affinity LXR ligands with excellent agonist potency and efficacy in functional assays of LXR activity were identified. In general, these sulfone agonists were equal to or superior to previously described alcohol and amide analogs in terms of affinity, functional potency, and microsomal stability. Many of the sulfones had LXRbeta binding IC(50) values <10nM while the most potent compounds in an ABCA1 mRNA induction assay in J774 mouse cells had EC(50) values <10nM and were as efficacious as T0901317.
Asunto(s)
Receptores Nucleares Huérfanos/agonistas , Quinolinas/química , Sulfonas/química , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Sitios de Unión , Línea Celular , Simulación por Computador , Humanos , Hidrocarburos Fluorados/química , Hidrocarburos Fluorados/farmacología , Enlace de Hidrógeno , Receptores X del Hígado , Ratones , Microsomas Hepáticos/metabolismo , Receptores Nucleares Huérfanos/metabolismo , Quinolinas/síntesis química , Quinolinas/farmacología , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonas/síntesis química , Sulfonas/farmacologíaRESUMEN
BACKGROUND: The largest health care-associated infection outbreak in the United States occurred during 2012-2013. Following injection of contaminated methylprednisolone, 753 patients developed infection with a dematiaceous mold, Exserohilum rostratum. The long-term outcomes of these infections have not been described. METHODS: This retrospective cohort study of 440 of a total of 753 patients with proven or probable Exserohilum infection evaluated clinical and radiographic findings, antifungal therapy and associated adverse effects, and outcomes at 6 weeks, 3, 6, 9, and 12 months after diagnosis. Patients were grouped into 4 disease categories: meningitis with/without stroke, spinal or paraspinal infections, meningitis/stroke plus spinal/paraspinal infections, and osteoarticular infections. RESULTS: Among the 440 patients, 223 (51%) had spinal/paraspinal infection, 82 (19%) meningitis/stroke, 123 (28%) both, and 12 (3%) osteoarticular infection. Of 82 patients with meningitis/stroke, 18 (22%) died; among those surviving, 87% were cured at 12 months. Only 7 (3%) of 223 patients with spinal/paraspinal infection died, but at 12 months, 68% had persistent or worsening pain and only 47% were cured. For the 123 patients with both meningitis/stroke and spinal/paraspinal infection, 10 (8%) died, pain persisted in 72%, and 52% were cured at 12 months. Only 37% of those with osteoarticular infection were cured at 12 months. Adverse events from antifungal therapy were noted at 6 weeks in 71% of patients on voriconazole and 81% on amphotericin B. CONCLUSIONS: Fungal infections related to contaminated methylprednisolone injections culminated in death in 8% of patients. Persistent pain and disability were seen at 12 months in most patients with spinal/paraspinal infections.
RESUMEN
A series of 4-(amido-biarylether)-quinolines was prepared as potential LXR agonists. Appropriate substitution with amide groups provided high affinity LXR ligands, some with excellent potency and efficacy in functional assays of LXR activity. Novel amide 4g had a binding IC(50)=1.9 nM for LXRbeta and EC(50)=34 nM (96% efficacy relative to T0901317) in an ABCA1 gene expression assay in mouse J774 cells, demonstrating that 4-(biarylether)-quinolines with appropriate amide substitution are potent LXR agonists.
Asunto(s)
Proteínas de Unión al ADN/agonistas , Quinolinas/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/biosíntesis , Transportadoras de Casetes de Unión a ATP/genética , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Línea Celular , Cristalografía por Rayos X , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica/efectos de los fármacos , Cinética , Ligandos , Receptores X del Hígado , Ratones , Modelos Moleculares , Receptores Nucleares Huérfanos , Quinolinas/síntesis química , Quinolinas/química , Receptores Citoplasmáticos y Nucleares/química , Receptores Citoplasmáticos y Nucleares/genética , Activación Transcripcional/efectos de los fármacos , TransfecciónRESUMEN
A series of 4-(3-aryloxyaryl)quinolines with alcohol substituents on the terminal aryl ring was prepared as potential LXR agonists, in which an alcohol group replaced an amide in previously reported amide analogs. High affinity LXR ligands with excellent agonist potency and efficacy in a functional model of LXR activity were identified, demonstrating that alcohols can substitute for amides while retaining LXR activity. The most potent compound was 5b which had an IC(50)=3.3 nM for LXRbeta binding and EC(50)=12 nM (122% efficacy relative to T0901317) in an ABCA1 mRNA induction assay in J774 mouse cells.
Asunto(s)
Alcoholes/síntesis química , Modelos Moleculares , Receptores Nucleares Huérfanos/metabolismo , Quinolinas/síntesis química , Alcoholes/química , Alcoholes/farmacología , Animales , Unión Competitiva/fisiología , Línea Celular , Receptores X del Hígado , Macrófagos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Receptores Nucleares Huérfanos/agonistas , Quinolinas/química , Quinolinas/farmacologíaRESUMEN
A series of 2-(4-hydroxy-phenyl)-benzofuran-5-ols with relatively lipophilic groups in the 7-position of the benzofuran was prepared and the affinity and selectivity for ER beta was measured. Many of the analogues were found to be potent and selective ER beta ligands. Additional modifications at the benzofuran 4-position as well as at the 3'-position of the 2-phenyl group were found to further increase selectivity. Such modifications led to compounds with <10 nM potency and >100-fold selectivity for ER beta.