RESUMO
A library of 72 compounds related to N- [4-(benzyloxy) benzoyl]alanine (I) was synthesized, prepared and screened for alpha-glucosidase inhibitory activity. Four compounds showed potent inhibition, six compounds moderate inhibition, and 16 were weak inhibitors. One compound, N- [4-(benzyloxy) benzoyl] serine, was found to be a potent inhibitor of alpha-glucosidase with 100% inhibition at 1 micro M. This inhibitor was at least five times more potent than the lead compound I.
Assuntos
Técnicas de Química Combinatória , Inibidores Enzimáticos/síntese química , Inibidores de Glicosídeo Hidrolases , Alanina , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologiaRESUMO
The 3-substituted phenyl-5-isoxazolecarboxaldehydes have been identified as activated aldehydes for the generation of isoxazole-based combinatorial libraries on solid phase through automation. Three highly functionalized isoxazole-based libraries comprising of 32, 96 and 45 compounds each have been synthesized in parallel format using Baylis Hillman reaction, Michael addition, reductive amination and alkylation reactions. With an objective of lead generation all the three libraries were evaluated for their antithrombin activity in vivo.
Assuntos
Fibrinolíticos/síntese química , Fibrinolíticos/farmacologia , Isoxazóis/química , Isoxazóis/farmacologia , Aldeídos/química , Animais , Tempo de Sangramento , Técnicas de Química Combinatória , Bases de Dados Factuais , Avaliação Pré-Clínica de Medicamentos , Camundongos , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Relação Estrutura-Atividade , Trombose Venosa/induzido quimicamenteRESUMO
Daily haloperidol injection at the dose of 5 mg/kg for 34 days did not change the levels of dopamine in the corpus striatum, frontal cortex, and midbrain of rats. However, the gamma-aminobutyric acid (GABA) level was increased by 27% in the corpus striatum. Haloperidol withdrawal for 4 days after 30-day treatment increased GABA levels of the corpus striatum and the frontal cortex to 140 and 125%, respectively, of control values. GABA, by its inhibitory actions, depleted dopamine level in the corpus striatum and frontal cortex by 17 and 29%, respectively. Administration of SL76002, a new GABA agonist, for 4 days at the dose of 400 mg/kg i.p. to haloperidol-withdrawn rats increased GABA levels in striatum by 23% of control values. The dopamine levels were also decreased significantly in the frontal cortex and corpus striatum. Our data demonstrate that SL76002, by altering the GABA levels, probably influences DA functioning in the corpus striatum, a region responsible for involuntary movements.