Synthesis and biological evaluation of novel pyrazoles and indazoles as activators of the nitric oxide receptor, soluble guanylate cyclase

Database searching and compound screening identified 1-benzyl-3-(3-dimethyl aminopropyloxy)-indazole (benzydamine, 3) as a potent activator of the nitr ic oxide receptor, soluble guanylate cyclase. A comprehensive structure-act ivity relationship study surrounding 3 clearly showed that the indazole C-3 dimethylaminopropyloxy substituent was critical for enzyme activity. Howev er replacement of the indazole ring of 3 by appropriately substituted pyraz oles maintained enzyme activity. Compounds were evaluated for inhibition of platelet aggregation and showed a general lipophilicity requirement. Aryl- substituted pyrazoles 32, 34, and 43 demonstrated potent activation of solu ble guanylate cyclase and potent inhibition of platelet aggregation. Pharma cokinetic studies in rats showed that compound 32 exhibits modest oral bioa vailability (12%). Furthermore 32 has an excellent selectivity profile nota bly showing no significant inhibition of phosphodiesterases or nitric oxide synthases.