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 that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of ß-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((4'-(trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose-dependent stimulation of insulin secretion in rodents.
Asunto(s)
Compuestos de Bifenilo/farmacología , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Disponibilidad Biológica , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/química , Relación Dosis-Respuesta a Droga , Ratones , Ratones Noqueados , Estructura Molecular , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Quinasas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Inhibidores Enzimáticos/química , Humanos , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/antagonistas & inhibidoresRESUMEN
A total synthesis of the vancomycin aglycon 1 has eluded synthetic chemists for so many years that the preparation of this molecule has become a vendetta for some groups. Finally, and almost simultaneously, research teams led by Evans and by Nicolaou have succeeded. Similarities and differences in their synthetic approaches are highlighted herein.
