RESUMO
In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.
Assuntos
Benzofuranos/farmacologia , Fibrinolíticos/farmacologia , Hemorragia/prevenção & controle , Receptores de Trombina/antagonistas & inibidores , Trombose/prevenção & controle , Animais , Benzofuranos/química , Benzofuranos/farmacocinética , Disponibilidade Biológica , Modelos Animais de Doenças , Fibrinolíticos/química , Fibrinolíticos/farmacocinética , Células HEK293 , Hemorragia/metabolismo , Humanos , Macaca fascicularis , Modelos Químicos , Estrutura Molecular , Agregação Plaquetária/efeitos dos fármacos , Receptores de Trombina/genética , Receptores de Trombina/metabolismo , Relação Estrutura-Atividade , Trombose/metabolismoRESUMO
The introduction of an aryl ring onto the 4-position of the C-6 benzyl amino group of the Cdk inhibitor roscovitine (2), maintained the potent Cdk inhibition demonstrated by roscovitine (2) as well as greatly improving the antiproliferative activity. A series of C-6 biarylmethylamino derivatives was prepared addressing modifications on the C-6 biaryl rings, N-9 and C-2 positions to provide compounds that displayed potent cytotoxic activity against tumor cell lines. In particular, derivative 21h demonstrated a >750-fold improvement in the growth inhibition of HeLa cells compared to roscovitine (2).
Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Purinas/síntese química , Purinas/química , Roscovitina , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of 7-[1H-indol-2-yl]-2,3-dihydro-isoindol-1-ones designed to be inhibitors of VEGF-R2 kinase was synthesized and found to potently inhibit VEGF-R2 and Aurora-A kinases. The structure-based design, synthesis, and initial SAR of the series are discussed.
Assuntos
Indóis , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Aurora Quinase A , Aurora Quinases , Técnicas de Química Combinatória , Desenho de Fármacos , Indóis/síntese química , Indóis/farmacologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The N-amination of heterocyclic compounds 1a-k with O-benzoylhydroxylamine derivatives 5 was developed and demonstrated to be a superior alternative to existing N-amination methods. A structure-reactivity relationship study was performed on variously substituted O-benzoylhydroxylamine derivatives, leading to the discovery of the novel and more efficient aminating reagents 5h and 5i.
