RESUMO
A series of substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones was synthesized from amino alcohols or amino thiols and keto acids. A pharmacological model based on the results obtained with these compounds led to the synthesis and evaluation of a series of isoxazoles and other monocyclic compounds. These were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. The in vivo hypoglycemic efficacy and potency of these compounds were evaluated in a model of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus), the ob/ob mouse. 25a(2S) (SDZ PGU 693) was selected for further pharmacological studies.
Assuntos
Hipoglicemiantes/síntese química , Oxazóis/síntese química , Pirróis/síntese química , Tiazóis/síntese química , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Glucose/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculos/citologia , Oxazóis/química , Oxazóis/farmacologia , Pirróis/química , Pirróis/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
The need for new therapies to treat systemic fungal infections continues to rise. Naturally occurring hexapeptide echinocandin B (1) has shown potent antifungal activity via its inhibition of the synthesis of beta-1,3 glucan, a key fungal cell wall component. Although this series of agents has been limited thus far based on their physicochemical characteristics, we have found that the synthesis of analogues bearing an aminoproline residue in the 'northwest' position imparts greatly improved water solubility (> 5 mg/mL). The synthesis and structure-activity relationships (SAR) based on whole cell and upon in vivo activity of the series of compounds are reported.
Assuntos
Antifúngicos/síntese química , Antifúngicos/farmacologia , Proteínas Fúngicas , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Peptídeos , Doença Aguda , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Anfotericina B/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Candida/efeitos dos fármacos , Candidíase Vulvovaginal/tratamento farmacológico , Candidíase Vulvovaginal/microbiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Equinocandinas , Feminino , Camundongos , Testes de Sensibilidade Microbiana , Peptídeos Cíclicos/química , Prolina/química , Solubilidade , Relação Estrutura-Atividade , Leveduras/efeitos dos fármacosRESUMO
A novel series of matrix metalloproteinase (MMP) inhibitors is described. Incorporation of a terminal alpha-mercaptoketone or alpha-mercaptoalcohol in the zinc binding domain of a series of inhibitors led to compounds exhibiting low nanomolar activity against collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).