SYNTHESIS AND EVALUATION OF POLYCYCLIC PYRAZOLO[3,4-D]PYRIMIDINES AS PDE1 AND PDE5 CGMP PHOSPHODIESTERASE INHIBITORS

Polycyclic pyrazolo[3,4-d]pyrimidines (represented by 3 and 4) were sy nthesized as analogues of the recently reported polycyclic guanine pho sphodiesterase (PDE) inhibitors. From the structure-activity relations hip (SAR) development of a series of compounds, it was discovered that C-3 benzyl and N-2 methyl disubstitution on the pyrazole ring gave th e best combination of potency and selectivity for PDE1 and PDE5 cGMP P DEs as represented by compound 4c: PDE1, IC50 = 60 nM; PDE3, IC50 = 55 000 nM; PDE5, IC50 = 75 nM. These compounds were also evaluated in vi vo and found to be good orally active antihypertensives in laboratory animal models. Finally, comparisons were made of the in vitro and in v ivo profiles of the pyrazolo[3,4-d]pyrimidine compound 4c with those o f two representative guanine compounds.