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Synthesis and Evaluation of Polycyclic Pyrazolo[3,4-d]pyrimidines as PDE1 and PDE5 cGMP Phosphodiesterase Inhibitors

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journal contribution
posted on 19.12.1997, 00:00 by Yan Xia, Samuel Chackalamannil, Michael Czarniecki, Hsingan Tsai, Henry Vaccaro, Renee Cleven, John Cook, Ahmad Fawzi, Robert Watkins, Hongtao Zhang
Polycyclic pyrazolo[3,4-d]pyrimidines (represented by 3 and 4) were synthesized as analogues of the recently reported polycyclic guanine phosphodiesterase (PDE) inhibitors. From the structure−activity relationship (SAR) development of a series of compounds, it was discovered that C-3 benzyl and N-2 methyl disubstitution on the pyrazole ring gave the best combination of potency and selectivity for PDE1 and PDE5 cGMP PDEs as represented by compound 4c:  PDE1, IC50 = 60 nM; PDE3, IC50 = 55 000 nM; PDE5, IC50 = 75 nM. These compounds were also evaluated in vivo and found to be good orally active antihypertensives in laboratory animal models. Finally, comparisons were made of the in vitro and in vivo profiles of the pyrazolo[3,4-d]pyrimidine compound 4c with those of two representative guanine compounds.