191982-75-9Relevant academic research and scientific papers
Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male ED
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
, p. 2365 - 2369 (2007/10/03)
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.
Potent tetracyclic guanine inhibitors of PDE1 and PDE5 cyclic guanosine monophosphate phosphodiesterases with oral antihypertensive activity
Ahn, Ho-Sam,Bercovici, Ana,Boykow, George,Bronnenkant, Alan,Chackalamannil, Samuel,Chow, Jason,Cleven, Renee,Cook, John,Czarniecki, Michael,Domalski, Carol,Fawzi, Ahmad,Green, Michael,Gündes, Asli,Ho, Ginny,Laudicina, Malvina,Lindo, Neil,Ma, Ke,Manna, Mahua,McKittrick, Brian,Mirzai, Bita,Nechuta, Terry,Neustadt, Bernard,Puchalski, Chester,Pula, Kathryn,Silverman, Lisa,Smith, Elizabeth,Stamford, Andrew,Tedesco, Richard P.,Tsai, Hsingan,Tulshian, Deen,Vaccaro, Henry,Watkins, Robert W.,Weng, Xiaoyu,Witkowski, Joseph T.,Xia, Yan,Zhang, Hongtao
, p. 2196 - 2210 (2007/10/03)
Tetracyclic guanines have been shown to be potent and selective inhibitors of the cGMP-hydrolyzing enzymes PDE1 and PDE5. In general, these compounds are inactive or only weakly active as inhibitors of PDE3, which is a major isozyme involved in cAMP hydrolysis. Structureactivity relationships are developed at N-l, C-2, N-3, and N-5 on the core nucleus. Compound 31, with an IC50 of 70 pM, is the most potent inhibitor of PDE1, while 50, with an IC50 of 4 nM, is the most potent inhibitor of PDE5. Compounds 20, 22, 30, and 50 are potent dual inhibitors with IC50 values below 30 nM for both PDE1 and PDE5. Compounds 12, 20, and 28 reduced blood pressure by more than 45 mmHg when administered orally at 10 mg/kg to the spontaneously hypertensive rat (SHR).
