Potent tetracyclic guanine inhibitors of PDE1 and PDE5 cyclic guanosine monophosphate phosphodiesterases with oral antihypertensive activity

…, C Domalski, A Fawzi, M Green, A Gündes…

Index: 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; Guendes, 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 Journal of Medicinal Chemistry, 1997 , vol. 40, # 14 p. 2196 - 2210

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Citation Number: 103

Abstract

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. Structure-activity relationships are developed at N-1, 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 ...