RESUMO
The syntheses and SAR of new series of beta-amyloid binding agents are reported. The effort to optimize signal-to-background ratios for these ligands are described. Compounds 8, 21 and 30 displayed desirable lipophilicity and pharmacokinetic properties. Compounds 8 and 21 were evaluated with in vitro autoradiographic studies and in vivo in APP/PS1 transgenic mice. It is shown that it was possible to increase the signal-to-background ratios compared to PIB 1, as demonstrated by compounds 8 and 21.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Benzofuranos/síntese química , Benzofuranos/farmacocinética , Benzotiazóis/síntese química , Benzotiazóis/farmacocinética , Benzoxazóis/síntese química , Benzoxazóis/farmacocinética , Tomografia por Emissão de Pósitrons , Animais , Radioisótopos de Carbono , Meia-Vida , Camundongos , Camundongos Transgênicos , Ensaio Radioligante , Relação Estrutura-AtividadeRESUMO
The design and synthesis of a new series of c-Jun N-terminal kinase-3 (JNK3) inhibitors with selectivity against JNK1 are reported. The novel series of substituted 2'-anilino-4,4'-bipyridines were designed based on a combination of hits from high throughput screening and X-ray crystal structure information of compounds crystallized into the JNK3 ATP binding active site.
Assuntos
Compostos de Anilina/química , Desenho de Fármacos , Proteína Quinase 10 Ativada por Mitógeno/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Animais , Cristalografia por Raios X , Concentração Inibidora 50 , Proteína Quinase 10 Ativada por Mitógeno/química , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Terciária de Proteína , Piridinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis and in vitro cytotoxicity toward various tumor cell lines of (+/-)-tridemethylisovelleral, an analogue of the bioactive fungal sesquiterpene (+)-isovelleral retaining the bicyclo[4,1,0]hept-2-en-1,2-dicarbaldehyde system but lacking the three methyl groups, is reported. The cytotoxicity of tridemethylisovelleral toward several tumor cell lines was found to be comparable with those of established antitumor drugs, and significantly higher than that of isovelleral.