Synthesis and phosphodiesterase 5 inhibitory activity of new 5-phenyl-1,6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-one derivatives containing an N-acylamido group on a phenyl ring

New sildenafil analogues with an N-acylamido group at the 5'-position of the phenyl ring, 6a-e, were prepared from the readily available starting compound 2 in four straightforward steps. Enzyme assays demonstrated that all the target compounds 6a-e showed higher PDES inhibitory activities than sildenafil. It was observed that the PDES inhibitory activity was enhanced as the chain length of R group increased, but introduction of the branched alkyl groups such as isopropyl (6d) and cyclohexyl (6e) resulted in the drop of potency compared with 6c. In particular the N-butyrylamido derivative 6e exhibited the highest PDES inhibitory activity, and was about 6-fold more potent than sildenafil. However, all the compounds exhibited somewhat weak selectivity(1-3-fold) over PDE6, indicating that the compounds 6a-e have intrinsically lower selectivity than sildenafil. (C) 2001 Elsevier Science Ltd. All rights reserved.