RESUMEN
Selective small molecule inhibitors of Tie-2 kinase are important tools for the validation of Tie-2 signaling in pathological angiogenesis. Reported herein is the optimization of a nonselective scaffold into a potent and highly selective inhibitor of Tie-2 kinase.
Asunto(s)
Bencimidazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor TIE-2/antagonistas & inhibidores , Administración Oral , Bencimidazoles/administración & dosificación , Bencimidazoles/química , Disponibilidad Biológica , Cristalografía por Rayos X , Células HeLa , Humanos , Modelos Moleculares , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/químicaRESUMEN
11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is the enzyme that converts cortisone to cortisol. A growing body of evidence suggests that selective inhibition of 11beta-HSD1 could potentially treat metabolic syndrome as well as type 2 diabetes. Through modification of our initial lead 1, we have discovered trifluoromethyl thiazolone 17. This compound had a Ki of 22 nM, possessed low in vivo clearance, and showed a 91% inhibition of adipose 11beta-HSD1 enzymatic activity in a mouse ex vivo pharmacodynamic model.
Asunto(s)
Tiazoles/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , Tejido Adiposo/enzimología , Administración Oral , Animales , Disponibilidad Biológica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
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 recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.
Asunto(s)
Alquinos/síntesis química , Amidas/síntesis química , Inhibidores de la Angiogénesis/síntesis química , Pirimidinas/síntesis química , Receptor TIE-2/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Alquinos/farmacocinética , Alquinos/farmacología , Amidas/farmacocinética , Amidas/farmacología , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Sitios de Unión , Proteínas Sanguíneas/metabolismo , Línea Celular , Femenino , Humanos , Técnicas In Vitro , Pulmón/efectos de los fármacos , Pulmón/enzimología , Masculino , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Fosforilación , Unión Proteica , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor TIE-2/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of compounds containing the 2-amino-1,3-thiazol-4(5H)-one core were found to be potent inhibitors of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). One of our lead compounds from this series activated the human nuclear xenobiotic receptor, pregnane X receptor (PXR). To try and mitigate the PXR activity, we prepared analogues of our lead series that contained polar groups on the right-hand side of the thiazolone. Several analogues containing amides or alcohols appended to the C-5 position of the thiazolone showed a significant reduction in PXR activity. Through these structure-activity efforts, a compound containing a tert-alcohol group off the C-5 position, analogue (S)-33a, was found to have an 11beta-HSD1 Ki = 35 nM and negligible PXR activity. Compound (S)-33a was advanced into a pharmacodynamic model in cynomolgus monkeys, where it inhibited adipose 11beta-HSD1 activity after being orally administered.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Receptores de Esteroides/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , Animales , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Citocromo P-450 CYP3A/química , Diseño de Fármacos , Humanos , Cinética , Macaca fascicularis , Masculino , Modelos Moleculares , Conformación Molecular , Receptor X de Pregnano , Distribución TisularRESUMEN
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.