ABSTRACT
In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile.
Subject(s)
Erectile Dysfunction/drug therapy , Phosphodiesterase I/metabolism , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/therapeutic use , Phosphoric Diester Hydrolases/metabolism , Purines/chemical synthesis , Purines/therapeutic use , 3',5'-Cyclic-GMP Phosphodiesterases , Animals , Cyclic Nucleotide Phosphodiesterases, Type 5 , Humans , Male , Models, Molecular , Molecular Structure , Piperazines/pharmacology , Purines/chemistry , Rats , Sildenafil Citrate , Structure-Activity Relationship , Sulfones , Vasodilator Agents/chemical synthesis , Vasodilator Agents/pharmacology , Vasodilator Agents/therapeutic useABSTRACT
Development of structure-activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52-59 (IC50=1.3-11.0 nM, PDE6/5=116-600).
Subject(s)
3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , Drug Delivery Systems/methods , Erectile Dysfunction/drug therapy , Erectile Dysfunction/enzymology , Guanine/chemistry , Phosphodiesterase Inhibitors/chemistry , 3',5'-Cyclic-GMP Phosphodiesterases/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 5 , Guanine/administration & dosage , Humans , Male , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/therapeutic use , Polycyclic Compounds/administration & dosage , Polycyclic Compounds/chemistry , Structure-Activity RelationshipABSTRACT
We have discovered potent and selective xanthine PDE5 inhibitors. Compound 25 (PDE5 IC(50)=0.6 nM, PDE6/PDE5=101) demonstrated similar functional efficacy and PK profile to Sildenafil (PDE5 IC(50)=3.5 nM, PDE6/PDE5=7).
