RESUMO
A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.
Assuntos
Antifúngicos/química , Inibidores Enzimáticos/química , Glucosiltransferases/antagonistas & inibidores , Piridazinas/química , Sulfonamidas/química , Animais , Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Glucosiltransferases/metabolismo , Meia-Vida , Camundongos , Testes de Sensibilidade Microbiana , Piridazinas/farmacocinética , Piridazinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêuticoRESUMO
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
A novel series of pyridazinone analogs has been developed as potent ß-1,3-glucan synthase inhibitors through structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one (1). The effect of changes to the core structure is described in detail. Optimization of the sulfonamide moiety led to the identification of important compounds with much improved systematic exposure while retaining good antifungal activity against the fungal strains Candida glabrata and Candida albicans.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glucosiltransferases/antagonistas & inibidores , Piridazinas/síntese química , Piridazinas/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida glabrata/efeitos dos fármacos , Inibidores Enzimáticos/química , Estrutura Molecular , Piridazinas/química , Relação Estrutura-AtividadeRESUMO
A structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one 1 has resulted in the identification of 2-(3,5-difluorophenyl)-4-(3-fluorocyclopentyloxy)-5-[4-(isopropylsulfonyl)piperazin-1-yl]-pyridazin-3(2H)-one 11c as a ß-1,3-glucan synthase inhibitor. Compound 11c exhibited significant efficacy in an in vivo mouse model of Candida glabrata infection.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glucosiltransferases/antagonistas & inibidores , Piridazinas/química , Piridazinas/farmacologia , Inibidores Enzimáticos/síntese química , Piridazinas/síntese química , Relação Estrutura-AtividadeRESUMO
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
Packed-column supercritical fluid chromatography (pSFC) coupled to an atmospheric pressure chemical ionization (APCI) source and a tandem mass spectrometer (MS/MS) for rapid and simultaneous determination of clozapine, ondansetron, tolbutamide and primidone in in vitro samples was developed in support of metabolic stability experiments. The effects of the eluent flow-rate and composition as well as the nebulizer temperatures on the ionization efficiency of the analytes in positive ion mode under normal phase pSFC conditions were studied. The metabolic stability of the test drug components through microsomal incubation by the proposed pSFC-APCI/MS/MS approaches requiring approximately 1 min per samples were evaluated with respect to specificity, durability and accuracy. These metabolic stability results obtained by pSFC-MS/MS methods are in a good agreement with those obtained by fast high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method.
Assuntos
Preparações Farmacêuticas/análise , Animais , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Técnicas In Vitro , Indicadores e Reagentes , Espectrometria de Massas , Microssomos Hepáticos/metabolismo , Preparações Farmacêuticas/metabolismo , 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
We report the discovery of novel histamine H(3) receptor antagonists based on 4-[(1H-imidazol-4-yl)methyl]piperidine. The most potent compounds in the series (e.g., 7) result from the attachment of a substituted aniline amide to the main pharmacophore piperidine via a two-methylene linker.
Assuntos
Antagonistas dos Receptores Histamínicos/farmacologia , Imidazóis/farmacologia , Piperidinas/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP2D6 , Avaliação Pré-Clínica de Medicamentos , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/química , Humanos , Imidazóis/síntese química , Imidazóis/química , Técnicas In Vitro , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
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 structural modification of the benzylic ether region of oxime 1 has resulted in the identification of several novel aryl amides as selective or dual NK(1)/NK(2) antagonists.