RESUMO
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.
Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Compostos Heterocíclicos com 3 Anéis/síntese química , Naftiridinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Cães , Descoberta de Drogas , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Macaca fascicularis , Naftiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Ratos , Relação Estrutura-Atividade , Células U937 , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
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.
Assuntos
Benzodiazepinonas/síntese química , Química Farmacêutica/métodos , Receptores da Bombesina/antagonistas & inibidores , Animais , Benzodiazepinonas/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Elétrons , Peptídeo Liberador de Gastrina/química , Células HeLa , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Químicos , Peptídeos/química , Relação Estrutura-AtividadeRESUMO
The discovery and optimization of a series of potent PPARdelta full agonists with partial agonistic activity against PPARgamma is described.
Assuntos
PPAR delta/agonistas , PPAR gama/agonistas , Tiazóis/química , Animais , Simulação por Computador , Cristalografia por Raios X , PPAR delta/metabolismo , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
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.
