Synthesis and evaluation of polycyclic pyrazolo[3,4-d]pyrimidines as PDE1 and PDE5 cGMP phosphodiesterase inhibitors

Journal of Medicinal Chemistry
Y XiaH Zhang

Abstract

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.

Citations

Jun 8, 2014·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Ahmed H AbdelazeemSamir M El-Moghazy
Apr 14, 2017·Journal of Medicinal Chemistry·Brian DyckAli Tabatabaei
Oct 14, 2017·Future Medicinal Chemistry·Kamal Fahmy Mohamed AttaEl Sayed Helmy El Ashry
Feb 15, 2018·Beilstein Journal of Organic Chemistry·Ranjana Aggarwal, Suresh Kumar
Dec 15, 2015·Beilstein Journal of Organic Chemistry·Mingxing LiuDaxin Shi
Jan 8, 2021·European Journal of Medicinal Chemistry·Nathalia Fonseca NadurArthur Eugen Kümmerle
Jun 20, 2018·Journal of Medicinal Chemistry·Dean G Brown, Jonas Boström

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