RESUMEN
RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Animales , Benzazepinas/química , Benzazepinas/farmacología , Colitis Ulcerosa/inmunología , Citocinas/inmunología , Perros , Haplorrinos , Humanos , Inflamación/inmunología , Ratones , Simulación del Acoplamiento Molecular , Conejos , Ratas , Proteína Serina-Treonina Quinasas de Interacción con Receptores/inmunología , Porcinos , Porcinos Enanos , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Replacement of a quinoline with an imidazo[1,2-a]pyridine in a series of liver X receptor (LXR) agonists incorporating a [3-(sulfonyl)aryloxyphenyl] side chain provided high affinity LXR ligands 7. In functional assays of LXR activity, good agonist potency and efficacy were found for several analogs.
Asunto(s)
Receptores Nucleares Huérfanos/agonistas , Piridinas/síntesis química , Quinolinas/síntesis química , Sulfonas/síntesis química , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Células Hep G2 , Humanos , Receptores X del Hígado , Ratones , Microsomas Hepáticos/metabolismo , Receptores Nucleares Huérfanos/metabolismo , Unión Proteica , Piridinas/química , Piridinas/farmacología , Quinolinas/química , Quinolinas/farmacología , ARN Mensajero/metabolismo , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
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
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 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
The design, synthesis, and biological evaluation of the 2-phenyl-isoindole-1,3-diones will be discussed. Detailed modeling studies with X-ray support were used to understand the ligand binding orientation and observed selectivity.
Asunto(s)
Receptor beta de Estrógeno/agonistas , Indoles/química , Ftalimidas/química , Cristalografía por Rayos X , Receptor beta de Estrógeno/química , Humanos , Indoles/síntesis química , Ligandos , Ftalimidas/síntesis químicaRESUMEN
The synthesis of an unnatural amino acid, 1-amino-3-[2-(1,7-dicarba-closo-dodecaboran(12)-1-yl)ethyl]cyclobutanecarboxylic acid, was achieved. This new potential BNCT agent was prepared via the monoalkylation of m-carborane with 4-bromobutene to produce 4-m-carboranyl-1-butene, which was then subjected to a 2 + 2 cycloaddition using dichloroketene. The resultant boronated cyclobutanone was reductively dechlorinated prior to the formation of the corresponding hydantoin, which was hydrolized to the title compound in excellent yield.
