ABSTRACT
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 SpecificitySubject(s)
Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/chemistry , 3',5'-Cyclic-GMP Phosphodiesterases , Cyclic GMP/physiology , Cyclic Nucleotide Phosphodiesterases, Type 5 , Erectile Dysfunction/drug therapy , Humans , Hypertension, Pulmonary/drug therapy , Male , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/therapeutic use , Phosphoric Diester Hydrolases/genetics , Phosphoric Diester Hydrolases/physiology , Pyrimidinones/pharmacology , Structure-Activity RelationshipABSTRACT
Chronic hepatitis B virus (HBV) infection is a major cause of liver disease. Only interferon-alpha and the nucleosidic inhibitors of the viral polymerase, 3TC and adefovir, are approved for therapy. However, these therapies are limited by the side effects of interferon and the substantial resistance of the virus to nucleosidic inhibitors. Potent new antiviral compounds suitable for monotherapy or combination therapy are highly desired. We describe non-nucleosidic inhibitors of HBV nucleocapsid maturation that possess in vitro and in vivo antiviral activity. These inhibitors have potential for future therapeutic regimens to combat chronic HBV infection.
Subject(s)
Acetylcysteine/analogs & derivatives , Antiviral Agents/pharmacology , Hepatitis B virus/drug effects , Nucleocapsid/metabolism , Pyridines/pharmacology , Pyrimidines/pharmacology , Triazoles/pharmacology , Acetylcysteine/pharmacology , Amino Acid Substitution , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Binding Sites , Capsid/metabolism , DNA Replication/drug effects , DNA, Viral/biosynthesis , Half-Life , Hepatitis B Virus, Duck/drug effects , Hepatitis B Virus, Duck/metabolism , Hepatitis B virus/physiology , Humans , Mutation , Pyridines/chemistry , Pyridines/metabolism , Pyrimidines/chemistry , Pyrimidines/metabolism , Recombinant Proteins/metabolism , Stereoisomerism , Triazoles/chemistry , Triazoles/metabolism , Tumor Cells, Cultured , Viral Core Proteins/chemistry , Viral Core Proteins/genetics , Viral Core Proteins/metabolism , Virus Assembly/drug effects , Virus Replication/drug effectsABSTRACT
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.
