RESUMO
A series of novel, potent and selective pyrido[1,2-a]pyrazine dopamine D4 receptor antagonists are reported including CP-293,019 (D4 Ki = 3.4 nM, D2 Ki > 3,310 nM), which also inhibits apomorphine-induced hyperlocomotion in rats after oral dosing.
Assuntos
Antagonistas de Dopamina/síntese química , Antagonistas dos Receptores de Dopamina D2 , Atividade Motora/efeitos dos fármacos , Pirazinas/síntese química , Pirimidinas/síntese química , Animais , Apomorfina/farmacologia , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Desenho de Fármacos , Haloperidol/farmacologia , Indicadores e Reagentes , Estrutura Molecular , Pirazinas/química , Pirazinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Receptores de Dopamina D4 , Relação Estrutura-AtividadeRESUMO
Guanidinothiazolecarboxamides (GTCs) are a novel class of antitumor agents found to be systemically active against experimental pulmonary metastases of 3LL Lewis lung carcinoma. A series of substituted benzothiazole GTCs were found to produce enhancement of survival in this model by using 8 days of intraperitoneal dosing initiated 2 days after intravenous tumor challenge. Quantitative structure-activity relationships have been discovered in the GTC series with survival enhancement correlated to substituent parameters. Optimal correlations were found between the probit transform of the drug-induced increased lifespan (ILS) and field and pi parameters. Among the most effective analogues in this series was N-(5-fluorobenzothiazol-2-yl)-2-guanidinothiazole-4-carboxam ide.
Assuntos
Antineoplásicos/síntese química , Guanidinas/síntese química , Tiazóis/síntese química , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Animais , Antineoplásicos/uso terapêutico , Fenômenos Químicos , Química , Feminino , Guanidinas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Camundongos , Modelos Biológicos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/mortalidade , Relação Estrutura-Atividade , Tiazóis/uso terapêuticoRESUMO
N-(5-Fluorobenzothiazol-2-yl)-2-guanidinothiazole-4-carboxam ide (1) is a member of a series of amides found to substantially increase lifespan in mice bearing established micrometastatic 3LL Lewis lung carcinoma. Amide 1 is effective after either oral or intraperitoneal dosing in acute, subacute, or chronic regimens. 1 is well tolerated in this model with an excellent therapeutic index relative to the cytotoxic anticancer drug adriamycin.