Studies On The Design, Synthesis Of Pyrazolopyrimidinones And Their Pharmacological Activities

Both adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic mono-phosphate (cGMP) are intracellular second messengers, which play important roles in cell signaling. Their intracellular concentrations are regulated predominantly by cyclic nucleotide phosphodiesterase (PDE) enzymes. At least 11 families of distinct PDE isoenzymes are known, and these enzymes differ with respect to tissue distribution, substrate specificity and sensitivity to selective inhibitors. There is a wide distribution of these enzymes throughout the body. Inhibitors of PDEs regulate the function of many tissues by inhibiting the PDEs activities and elevating the intracellular cAMP and cGMP levels. Inhibitors of PDE3, PDE4, PDE5 are used widely in clinical treatment. Selective PDE5 inhibitors may mediate intracellular cGMP level, and they can be used not only for the treatment of male sexual dysfunction, but also as antihypertensive, anti-angina pectoris, anti-thrombotic and anti-asthma agents.Pyrazolopyrimidinones exhibit selectivity for inhibition of PDE5, and these compounds bear some similarities with the cGMP basic structure, the later is the specific substrate of PDE5. According to the structure activity relationship of this series of compounds reported in literature, 46 new pyrazolopyrimidinone derivatives were designed and synthesized and their structures were confirmed by IR, 1H-NMR, 13C-NMR, and MS.The relaxant effects on isolated rabbit aortic strips of these derivatives, as well as on isolated guinea pig tracheal strips, were evaluated. Among the compounds, PID-16 displayed outstanding relaxant effect (25.83%) on aortic strips, while that of control compound verapamil was 14.28%. Compound PID-29 (41.6%) on the isolated guinea pig tracheal strips was proved to be more active than the control aminophylline (38.8%). Compound PID-28 also shown potent relaxant activity on the tracheal strips, which was comparable with aminophylline.The structure-activity relationship of these compounds vas summarized. Comparative molecular field analysis (CoMFA), a three-dimensional quantitati-e structure activity relationship (3D-QSAR) paradigm, was used to study the correlations between the physio-chemical properties and the in vitro activities of these pyrazolopyrimidinones. The experimental and theoretical observations made in the present study should provide useful information for design of new type of PDE5 inhibitors.