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1.
J Med Chem ; 60(23): 9676-9690, 2017 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-29156136

RESUMEN

The discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the discovery of compound 28.


Asunto(s)
Janus Quinasa 1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/química , Pirazoles/farmacología , Animales , Perros , Descubrimiento de Drogas , Halogenación , Humanos , Janus Quinasa 1/química , Janus Quinasa 1/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/administración & dosificación , Pirazoles/farmacocinética , Ratas , Relación Estructura-Actividad
2.
Bioorg Med Chem Lett ; 25(17): 3495-500, 2015 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-26142947

RESUMEN

The triazolyl amide γ-secretase modulators are potent alternatives to the cinnamyl amides that have entered the clinic for the treatment of Alzheimer's disease. Herein we build on the lead benzoazepinones described in our prior communication with imidazomethoxyarene moiety alternatives that offer opportunities to fine tune physical properties as well as address hERG binding and PK. Both half-life and bioavailability were significantly improved, especially in dog, with robust brain Aß42 lowering maintained in both transgenic mouse and rat.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/farmacocinética , Animales , Disponibilidad Biológica , Ratones , Ratones Transgénicos , Ratas
3.
Bioorg Med Chem Lett ; 21(13): 4083-7, 2011 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-21616665

RESUMEN

Synthesis, SAR, and evaluation of aryl triazoles as novel gamma secretase modulators (GSMs) are presented in this communication. Starting from the literature and in-house leads, we evaluated a range of five-membered heterocycles as replacements for olefins commonly found in non-acid GSMs. 1,2,3-C-aryl-triazoles were identified as suitable replacements which exhibited good modulation of γ-secretase activity, excellent pharmacokinetics and good central lowering of Aß42 in Sprague-Dawley rats.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Triazoles/síntesis química , Triazoles/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Estructura Molecular , Unión Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Triazoles/metabolismo
4.
Bioorg Med Chem Lett ; 18(23): 6104-9, 2008 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-18951790

RESUMEN

A potent family of spirocyclic nicotinyl aminobenzamide selective HDAC1/HDAC2 inhibitors (SHI-1:2) is profiled. The incorporation of a biaryl zinc-binding motif into a nicotinyl scaffold resulted in enhanced potency and selectivity versus HDAC3, but also imparted hERG activity. It was discovered that increasing polar surface area about the spirocycle attenuates this liability. Compound 12 induced a 4-fold increase in acetylated histone H2B in an HCT-116 xenograft model study with acute exposure, and inhibited tumor growth in a 21-day efficacy study with qd dosing.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Canales de Potasio Éter-A-Go-Go/metabolismo , Inhibidores de Histona Desacetilasas , Niacinamida/síntesis química , Niacinamida/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Animales , Antineoplásicos/química , Benzamidas/síntesis química , Benzamidas/química , Benzamidas/farmacología , Técnicas Químicas Combinatorias , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Células HCT116 , Histona Desacetilasas , Histonas/análisis , Humanos , Ratones , Ratones Desnudos , Estructura Molecular , Niacinamida/química , Isoformas de Proteínas , Compuestos de Espiro/química , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Bioorg Med Chem Lett ; 17(19): 5300-9, 2007 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-17761416

RESUMEN

This communication highlights the development of a nicotinamide series of histone deacetylase inhibitors within the benzamide structural class. Extensive exploration around the nicotinamide core led to the discovery of a class I selective HDAC inhibitor that possesses excellent intrinsic and cell-based potency, acceptable ancillary pharmacology, favorable pharmacokinetics, sustained pharmacodynamics in vitro, and achieves in vivo efficacy in an HCT116 xenograft model.


Asunto(s)
6-Aminonicotinamida/análogos & derivados , 6-Aminonicotinamida/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , 6-Aminonicotinamida/síntesis química , Animales , Área Bajo la Curva , Benzamidas/química , Disponibilidad Biológica , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Perros , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/farmacocinética , Semivida , Humanos , Isoenzimas/antagonistas & inhibidores , Modelos Moleculares , Trasplante de Neoplasias , Unión Proteica , Ratas , Relación Estructura-Actividad , Especificidad por Sustrato
6.
J Am Chem Soc ; 127(13): 4584-5, 2005 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-15796518

RESUMEN

The first examples of catalytic asymmetric conjugate addition (ACA) of alkylzinc reagents to trisubstituted nitroalkenes, leading to the formation of nitroalkanes bearing a quaternary carbon stereogenic center, are reported. Reactions are promoted in the presence of 4 mol % of a readily available amino acid-based phosphine and 2 mol % (CuOTf).C6H6. Cu-catalyzed reactions proceed efficiently in up to 98% ee and can be carried out with a variety of dialkylzinc reagents and trisubstituted nitroolefins. We highlight the synthetic utility of the products obtained by efficient conversion of optically enriched nitroalkanes to the corresponding carboxylic acids.


Asunto(s)
Alcanos/síntesis química , Cobre/química , Nitrocompuestos/síntesis química , Compuestos Organometálicos/química , Alcanos/química , Catálisis , Nitrocompuestos/química , Estereoisomerismo
7.
Org Lett ; 6(16): 2829-32, 2004 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-15281780

RESUMEN

An efficient and highly enantioselective (up to 95% ee) Cu-catalyzed method for asymmetric conjugate addition (ACA) of alkylzinc reagents to acyclic disubstituted nitroalkenes is presented. Reactions are typically effected at ambient temperature in the presence of 2 mol % chiral dipeptide phosphine and 1 mol % (CuOTf)(2).C(6)H(6). Nitroalkenes bearing aromatic as well as aliphatic substituents readily undergo asymmetric additions. [reaction: see text]


Asunto(s)
Alquenos/química , Cobre/química , Cicloparafinas/química , Nitrocompuestos/química , Zinc/química , Alquilación , Aminas/química , Catálisis , Indicadores y Reactivos/química , Ligandos , Compuestos Organometálicos/química
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