RESUMO
Starting from natural product podophyllotoxin 1 substituted heterolignans were identified with promising insecticidal in vivo activity. The impact of substitution in each segment of the core structure was investigated in a detailed SAR study, and variation of substituents in both aromatic moieties afforded derivatives 5 and 43 with broad insecticidal activity against lepidopteran and coleopteran species. In vitro measurements supported by modeling studies indicate that heterolignans 3-134 act as tubuline polymerization inhibitors interacting with the colchicine-binding site. Insect specific structure-activity effects were observed showing that the insecticidal SAR described herein differs from reported cytotoxicity studies.
Assuntos
Inseticidas/química , Lignanas/química , Podofilotoxina/química , Moduladores de Tubulina/química , Animais , Besouros/efeitos dos fármacos , Simulação por Computador , Cristalografia por Raios X , Inseticidas/síntese química , Inseticidas/toxicidade , Lepidópteros/efeitos dos fármacos , Lignanas/síntese química , Lignanas/toxicidade , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/toxicidadeRESUMO
Several different heterocyclic systems were compared as PDE5 inhibitor scaffolds. In addition to the known 3H-imidazo[5,1-f][1,2,4]triazin-4-ones and pyrazolopyrimidinones, isomeric imidazo[1,5-a][1,3,5]triazin-4(3H)-ones were also shown to be potent and selective PDE inhibitor scaffolds with in vivo activity. SAR trends were elucidated for sulfonamide derivatives with generality across different scaffolds.
Assuntos
3',5'-GMP Cíclico Fosfodiesterases/antagonistas & inibidores , Compostos Heterocíclicos/síntese química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Compostos Heterocíclicos/farmacologia , Concentração Inibidora 50 , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
2-aryl-substituted imidazo[5,1-f][1,2,4]triazin-4(3H)-ones represent a new class of potent cGMP-PDE 5 inhibitors that prove to be superior to other purine-isosteric inhibitors. Subnanomolar inhibitors of PDE 5 with activity in in vivo models for erectile dysfunction have been identified. BAY 38-9456 (Vardenafil-hydrochloride) has been selected for clinical studies in the indication of erectile dysfunction.