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

摘要: Abstract Cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type-5 (PDE5), a clinically proven target to treat erectile dysfunction and diseases associated with lower cGMP levels in humans, is present corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, stomach. Sildenafil, vardenafil, tadalafil avanafil are FDA approved drugs market as PDE5 inhibitors for treating dysfunction. In the study 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 selective inhibitor. A series compounds was synthesized by replacing -methylpiperazine moiety (ring-C) sildenafil structure different -substitutions towards sulfonamide end. Compound- showed IC 50 value (1.5 nM) against than parent (5.6 nM) vitro enzyme assay. The isoform selectivity other PDE isoforms similar Sildenafil. corroboration data, this better efficacy vivo studies using conscious rabbit model. Also exhibited good physicochemical properties like solubility, caco-2 permeability, c  Log  P along optimal PK profile having no significant CYP inhibitory liabilities. Discovery these novel bioactive may open new alternative developing preclinical candidates based on drugable scaffold.