Abstract
A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.
MeSH terms
-
3',5'-Cyclic-GMP Phosphodiesterases
-
Animals
-
Catalytic Domain
-
Chemistry, Pharmaceutical / methods
-
Crystallography, X-Ray / methods
-
Cyclic Nucleotide Phosphodiesterases, Type 5 / chemistry*
-
Cyclic Nucleotide Phosphodiesterases, Type 6 / antagonists & inhibitors
-
Cyclic Nucleotide Phosphodiesterases, Type 6 / chemistry
-
Drug Design
-
Humans
-
Hydrogen-Ion Concentration
-
Inhibitory Concentration 50
-
Phosphodiesterase 5 Inhibitors*
-
Phosphodiesterase Inhibitors / chemical synthesis
-
Phosphodiesterase Inhibitors / pharmacology
-
Phosphoric Diester Hydrolases / chemistry
-
Protein Structure, Tertiary
-
Pyrazines / chemical synthesis*
-
Pyrazines / pharmacology
-
Rats
-
Structure-Activity Relationship
Substances
-
Phosphodiesterase 5 Inhibitors
-
Phosphodiesterase Inhibitors
-
Pyrazines
-
Phosphoric Diester Hydrolases
-
3',5'-Cyclic-GMP Phosphodiesterases
-
Cyclic Nucleotide Phosphodiesterases, Type 5
-
Cyclic Nucleotide Phosphodiesterases, Type 6
-
PDE11A protein, human