RESUMO
As part of a program to develop dopamine D4 antagonists for the treatment of schizophrenia, we discovered a series of 6- and 7-(phenylpiperazinyl)- and -(phenylpiperidinyl)methylbenzoxazinones through mass screening of our compound library. A structure-activity relationship SAR study was carried out involving substituents on the phenyl ring, and several selective D4 antagonists were identified. The 7-substituted benzoxazinones showed more activity in neurochemical and behavioral tests than the 6-substituted series. One of the most potent and selective compounds (26) was found to have potent activity in animal tests predictive of antipsychotic activity in humans after oral administration. This paper describes the SAR of the benzoxazinone series and the preclinical characterization of 26.
Assuntos
Antipsicóticos/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Oxazinas/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Antipsicóticos/química , Células CHO , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Cricetinae , Dopamina/biossíntese , Dopamina/metabolismo , Antagonistas de Dopamina/química , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Espectroscopia de Ressonância Magnética , Oxazinas/química , Ratos , Receptores de Dopamina D4RESUMO
A series of [4-[2(4-arylpiperazin-1-yl)alkyl]cyclohexyl]pyrimidin-2-ylamine s was prepared and found to have receptor binding affinity for D2 and D3 dopamine (DA) receptors and serotonin 5-HT1A receptors. The structural contributions to D2/D3 and 5-HT1A receptor binding of the aminopyrimidine, cycloalkyl, and phenylpiperazine portions of the molecule were examined. From these studies compounds 14, 39, 42, 43, having potent affinity for both DA D2 and 5-HT1A receptors, were evaluated for intrinsic activity at these receptors, in vitro and in vivo. Compound 14 (PD 158771) had a profile indicative of partial agonist activity at both D2 and 5-HT1A receptors causing partially decreased synthesis of the neurotransmitters DA and 5-HT and their metabolites. This compound has a profile in behavioral tests that is predictive of antipsychotic activity, suggesting that mixed partial agonists such as 14 may have utility as antipsychotic agents with increased efficacy and decreased side effects.
Assuntos
Piperazinas/síntese química , Piperazinas/metabolismo , Pirimidinas/síntese química , Pirimidinas/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/metabolismo , Animais , Células CHO , Cricetinae , Cristalografia por Raios X , Humanos , Masculino , Camundongos , Conformação Molecular , Estrutura Molecular , Piperazinas/química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3 , Proteínas Recombinantes/metabolismo , Saimiri , Relação Estrutura-AtividadeRESUMO
PD 108635 (1) was identified as a potent dopamine D4 ligand and we wanted to replace the benzylic alcohol with a metabolically more stable moiety. Investigations led to the discovery of a series of isoindolinones having D4 affinity.
Assuntos
Indóis/química , Indóis/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Atividade Motora/efeitos dos fármacos , Ratos , Receptores de Dopamina D4 , Receptores de Serotonina/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Difração de Raios XRESUMO
A series of styrylpyrazoles, styrylisoxazoles, and styrylisothiazoles were prepared and found to be dual inhibitors of 5-lipoxygenase and cyclooxygenase in rat basophilic leukemia cells. Compounds from this series also were found to inhibit the in vivo production of LTB4 when dosed orally in rats. Among these compounds, di-tert-butylphenols 19 and 33 exhibit oral activity in various models of inflammation and, most importantly, are devoid of ulcerogenic potential.
