Phosphodiesterase 5 (PDE 5) inhibitors for the treatment of male erectile disorder: attaining selectivity versus PDE6.
The role of phosphodiesterase type 5 (PDE5) in the mechanism of male erection has been well understood, and several drugs inhibiting this enzyme are being used for the treatment of erectile dysfunction (ED). Discovery of inhibitors with improved selectivity versus other PDE isozymes could lead to drugs with improved safety profile. Achievement of selectivity versus PDE6, co-inhibition of which results in disturbances of color perception, remains the most challenging aspect of current drug discovery programs. The present review describes several case studies, where significant (>100 fold) selectivity versus PDE6 has been attained via investigation of structure-activity relationships (SAR). Special attention is given to the chemical routes leading to novel chemotypes and allowing efficient exploration of their SAR's. Strategies for attaining inhibitor selectivity discussed below may be applicable for other drug discovery programs.
Pissarnitski
Dmitri
D
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. Dmitri.Pissarnitski@spcorp.com
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D007172:Erectile Dysfunction / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D012680:Sensitivity and Specificity
D004791:Enzyme Inhibitors; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517381:PDE5A protein, human; C517431:PDE6B protein, human