Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5.

Abstract Cyclic guanosine monophosphate( cGMP) specific phosphodiesterase type-5(PDE5), a clinically proven target to treat erectile dysfunctionand diseases associated with lower cGMP levels in humans, is present in corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach. Sildenafil, vardenafil, tadalafiland avanafilare FDA approved drugsin market as PDE5 inhibitors for treating erectile dysfunction. In the present study a lead molecule 4-ethoxy- N -(6-hydroxyhexyl)-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1 H -pyrazolo[4,3- d ]pyrimidin-5-yl)benzenesulfonamide, that is, compound- 4a , an analog of pyrazolopyrimidinone scaffold has been identified as selective PDE5 inhibitor. A series of compounds was synthesized by replacing N -methylpiperazine moiety (ring-C) of sildenafilstructure with different N -substitutions towards sulfonamide end. Compound- 4a showed lower IC 50 value (1.5 nM) against PDE5 than parent sildenafil(5.6 nM) in in vitro enzyme assay. The isoform selectivity of the compound- 4a against other PDE isoforms was similar to that of the Sildenafil. In corroboration with the in vitro data, this molecule showed better efficacy in in vivo studies using the conscious rabbit model. Also compound- 4a exhibited good physicochemical properties like solubility, caco-2 permeability, c Log P along with optimal PK profile having no significant CYP enzyme inhibitory liabilities. Discovery of these novel bioactive compounds may open a new alternative for developing novel preclinical candidates based on this drugable scaffold.