RESUMEN
Herein we describe a general three-step synthesis of 4-substituted chlorophthalazines in good overall yields. In the key step, N,N-dimethylaminophthalimide (8a) directs the selective monoaddition of alkyl, aryl, and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones 9b, 9i-9am. Many of these hydroxyisoindolinones are converted to chlorophthalazines 1b-1v via reaction with hydrazine, followed by chlorination with POCl(3). We have also discovered two novel transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones. Addition of vinyl organometallic reagents to N,N-dimethylaminophthalimide (8a) provided dihydrobenzoazepinediones 15a-15c via the proposed ring expansion of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones react with hydrazine and substituted hydrazines to afford 2-pyrazolyl benzoic acids 16a-16d and 2-pyrazolyl benzohydrazides 17a-17g rather than the expected alkynyl phthalazinones.
Asunto(s)
Benzoatos/química , Benzoatos/síntesis química , Hidrazinas/química , Hidrazinas/síntesis química , Isoindoles/química , Isoindoles/síntesis química , Ftalazinas/química , Ftalazinas/síntesis química , Ftalimidas/química , Pirazoles/química , Pirazoles/síntesis química , Catálisis , Halogenación , Estructura Molecular , EstereoisomerismoRESUMEN
The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.
Asunto(s)
Antineoplásicos/síntesis química , Ftalazinas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridinas/síntesis química , Pirimidinas/síntesis química , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Aurora Quinasa B , Aurora Quinasas , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Histonas/metabolismo , Humanos , Técnicas In Vitro , Masculino , Ratones , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Trasplante de Neoplasias , Ftalazinas/farmacocinética , Ftalazinas/farmacología , Unión Proteica , Piridinas/farmacocinética , Piridinas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
A novel class of selective Tie-2 inhibitors was derived from a multi-kinase inhibitor 1. By reversing the amide connectivity and incorporating aminotriazine or aminopyridine hinge-binding moieties, excellent Tie-2 potency and KDR selectivity could be achieved with 3-substituted terminal aryl rings. X-ray co-crystal structure analysis aided inhibitor design. This series was evaluated on the basis of potency, selectivity, and rat pharmacokinetic parameters.
Asunto(s)
Receptor TIE-2/antagonistas & inhibidores , Triazinas/farmacología , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Masculino , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Receptor TIE-2/química , Relación Estructura-Actividad , Triazinas/químicaRESUMEN
Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Benzamidas/síntesis química , Piridinas/síntesis química , Receptor TIE-2/antagonistas & inhibidores , Triazinas/síntesis química , Administración Oral , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Benzamidas/farmacocinética , Benzamidas/farmacología , Sitios de Unión , Proteínas Sanguíneas/metabolismo , Cristalografía por Rayos X , Femenino , Humanos , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Fosforilación , Unión Proteica , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor TIE-2/química , Receptor TIE-2/metabolismo , Relación Estructura-Actividad , Triazinas/farmacocinética , Triazinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED(50) of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.