RESUMO
The identification of a potent series of IKK-beta selective inhibitors based on an imidazothienopyrazine template and the oral efficacy of one such analog (22j) in the LPS-induced TNF-alpha release mouse model are described.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Pirazinas/química , Pirazinas/farmacologia , Animais , Células Cultivadas , Inibidores Enzimáticos/síntese química , Humanos , Camundongos , Pirazinas/síntese química , Relação Estrutura-AtividadeRESUMO
We have recently identified BMS-345541 (1) as a highly selective and potent inhibitor of IKK-2 (IC50 = 0.30 microM), which however was considerably less potent against IKK-1 (IC50 = 4.0 microM). In order to further explore the SAR around the imidazoquinoxaline tricyclic structure of 1, we prepared a series of tetracyclic analogues (7, 13, and 18). The synthesis and biological activities of these potent IKK inhibitors are described.
Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Linhagem Celular , Humanos , Concentração Inibidora 50 , Quinazolinas/síntese química , Quinazolinas/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Quinoxalinas/síntese química , Quinoxalinas/farmacologia , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
This theoretical article reviews the scientific literature regarding the phenomenon of auditory hallucinations of people who are with or without a psychiatric diagnosis. Based on the conceptual model of the Disability Creation Process (Fougeyrollas et al., 1998), the authors describe the factors and mechanisms involved in this phenomenon in a systemic perspective. Finally, the authors examine future directions in intervention and research to favor the social participation of people who hear voices.
Assuntos
Alucinações/reabilitação , Padrões de Prática Médica , Pesquisa , Alucinações/etiologia , Humanos , Fatores de Risco , Meio SocialRESUMO
Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against the insulin receptor is described. The in vitro and in vivo biological activity of this interesting compound is also reported.
Assuntos
Antineoplásicos/síntese química , Benzimidazóis/síntese química , Piridinas/síntese química , Piridonas/síntese química , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Haplorrinos , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Transplante de Neoplasias , Piridinas/química , Piridinas/farmacologia , Piridonas/química , Piridonas/farmacologia , Ratos , Receptor de Insulina/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
EM-652 (acolbifene) analogs have been synthesized as selective estrogen receptor modulators. Substitution on the nitrogen atom of these 2H-1-benzopyran derivatives has been studied for its influence on antiestrogenic activity. Binding to the rat estrogen receptor, inhibition of estradiol-stimulated proliferation of T-47D breast cancer cells, as well as antiuterotrophic and uterotrophic activities in ovariectomized mice have been evaluated. 2H-1-Benzopyran 1b (EM-343, racemic form of EM-652), which contains a piperidine ring, shows the best pharmacological profile; RBA = 380, IC50 value = 0.110 nM (in T-47D cells), as well as 63% and 84% antiuterotrophic inhibitions at the 7.5 and 75 nmol doses, respectively.
