RESUMEN
We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
Asunto(s)
Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Naftiridinas/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Perros , Descubrimiento de Drogas , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Macaca fascicularis , Naftiridinas/farmacología , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Relación Estructura-Actividad , Células U937 , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
The discovery and parallel synthesis of potent, small molecule antagonists of Neuromedin B receptor based on the ary-hexahydro-dibenzodiazepin-1-one core is described.
Asunto(s)
Benzodiazepinonas/síntesis química , Química Farmacéutica/métodos , Receptores de Bombesina/antagonistas & inhibidores , Animales , Benzodiazepinonas/farmacología , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Electrones , Péptido Liberador de Gastrina/química , Células HeLa , Humanos , Concentración 50 Inhibidora , Ligandos , Modelos Químicos , Péptidos/química , Relación Estructura-ActividadRESUMEN
The discovery and optimization of a series of potent PPARdelta full agonists with partial agonistic activity against PPARgamma is described.
Asunto(s)
PPAR delta/agonistas , PPAR gamma/agonistas , Tiazoles/química , Animales , Simulación por Computador , Cristalografía por Rayos X , PPAR delta/metabolismo , PPAR gamma/metabolismo , Ratas , Ratas Sprague-Dawley , Tiazoles/síntesis química , Tiazoles/farmacologíaRESUMEN
This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.
