Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male ED

• Published in: Bioorganic & medicinal chemistry letters 2005-05, Vol.15 (9), p.2365-2369
• Main Authors: Boyle, Craig D., Xu, Ruo, Asberom, Theodros, Chackalamannil, Samuel, Clader, John W., Greenlee, William J., Guzik, Henry, Hu, Yuequing, Hu, Zhiyong, Lankin, Claire M., Pissarnitski, Dmitri A., Stamford, Andrew W., Wang, Yuguang, Skell, Jeffrey, Kurowski, Stanley, Vemulapalli, Subbarao, Palamanda, Jairam, Chintala, Madhu, Wu, Ping, Myers, Joyce, Wang, Peng
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Biological and medical sciences; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile dysfunction; Erectile Dysfunction - drug therapy; Genital system. Reproduction; Humans; Male; Male ED; Medical sciences; Models, Molecular; Molecular Structure; PDE5 inhibitor; Pharmacology. Drug treatments; Phosphodiesterase I - metabolism; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - therapeutic use; Phosphoric Diester Hydrolases - metabolism; Piperazines - pharmacology; Purine; Purines - chemical synthesis; Purines - chemistry; Purines - therapeutic use; Rats; Sildenafil Citrate; Structure-Activity Relationship; Sulfones; Vasodilator Agents - chemical synthesis; Vasodilator Agents - pharmacology; Vasodilator Agents - therapeutic use
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.02.083

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. 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.