RESUMO
Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.
Assuntos
Anti-Inflamatórios/síntese química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Oxazóis/síntese química , Inibidores da Fosfodiesterase 4/síntese química , Quinolinas/síntese química , Animais , Anti-Inflamatórios/farmacologia , Óxidos N-Cíclicos/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Descoberta de Drogas , Humanos , Modelos Moleculares , Oxazóis/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Substituted quinolyl oxazoles were discovered as a novel and highly potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationship studies revealed that the oxazole core, with 4-carboxamide and 5-aminomethyl groups, is a novel PDE4 inhibitory pharmacophore. Selectivity profiles and in vivo biological activity are also reported.
Assuntos
Oxazóis/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Modelos Moleculares , Oxazóis/química , Inibidores de Fosfodiesterase/química , RatosRESUMO
A series of novel five-membered urea derivatives as potent NK1 receptor antagonists is described. The effects of substitution of a 4-fluoro group at the phenyl ring and the introduction of an alpha-methyl group at the benzylic position to improve potency and duration of in vivo activity are discussed. Several compounds with high affinity and sustained in vivo activity were identified.
Assuntos
Ansiolíticos/química , Ansiolíticos/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Ansiolíticos/síntese química , Álcoois Benzílicos/química , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Flúor/química , Gerbillinae , Modelos Moleculares , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Relação Estrutura-Atividade , Ureia/síntese químicaRESUMO
A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Ureia/análogos & derivados , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Gerbillinae , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Compostos Heterocíclicos/farmacologia , Atividade Motora/efeitos dos fármacos , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Ureia/farmacocinética , Ureia/farmacologiaRESUMO
The synthesis and binding affinity for hNK(1) and hNK(2) receptors of a series of diacyl substituted 2-aryl piperazines are described. SAR evaluation led to the racemic derivative 11g as an apparent dual inhibitor. Chiral chromatographic separation of 11g led to the observation that NK(1) activity was shown by one enantiomer (13a) and NK(2) activity was shown by the other enantiomer (13b). X-ray crystallographic analysis of the crystalline di-BOC derivative of the NK(2) active piperazine (15) showed that the 2R configuration was associated with NK(2) activity. Further derivatization indicated that dual NK(1)/NK(2) activity could be built into the 2R series.
