ABSTRACT
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.
Subject(s)
Insecticides/chemistry , Lignans/chemistry , Podophyllotoxin/chemistry , Tubulin Modulators/chemistry , Animals , Coleoptera/drug effects , Computer Simulation , Crystallography, X-Ray , Insecticides/chemical synthesis , Insecticides/toxicity , Lepidoptera/drug effects , Lignans/chemical synthesis , Lignans/toxicity , Structure-Activity Relationship , Tubulin Modulators/chemical synthesis , Tubulin Modulators/toxicityABSTRACT
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.
Subject(s)
3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , Heterocyclic Compounds/chemical synthesis , Cyclic Nucleotide Phosphodiesterases, Type 5 , Heterocyclic Compounds/pharmacology , Inhibitory Concentration 50 , Structure-Activity Relationship , Substrate SpecificityABSTRACT
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.
