ABSTRACT
Database searching and compound screening identified 1-benzyl-3-(3-dimethylaminopropyloxy)indazole (benzydamine, 3) as a potent activator of the nitric oxide receptor, soluble guanylate cyclase. A comprehensive structure-activity relationship study surrounding 3 clearly showed that the indazole C-3 dimethylaminopropyloxy substituent was critical for enzyme activity. However replacement of the indazole ring of 3 by appropriately substituted pyrazoles 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 soluble guanylate cyclase and potent inhibition of platelet aggregation. Pharmacokinetic studies in rats showed that compound 32 exhibits modest oral bioavailability (12%). Furthermore 32 has an excellent selectivity profile notably showing no significant inhibition of phosphodiesterases or nitric oxide synthases.
Subject(s)
Guanylate Cyclase/metabolism , Indazoles/chemical synthesis , Nitric Oxide/metabolism , Pyrazoles/chemical synthesis , Animals , Enzyme Activation , Humans , In Vitro Techniques , Indazoles/chemistry , Indazoles/pharmacokinetics , Indazoles/pharmacology , Male , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Rats, Sprague-Dawley , Solubility , Structure-Activity RelationshipABSTRACT
Soluble guanylate cyclase (sGC) is an important component of the NO signaling pathway. Human sGC isoforms alpha(1), alpha(2), and beta(1) show differential mRNA tissue distributions. alpha(1) and beta(1) are expressed in most tissues; however, the alpha(2) isoform shows a more restricted expression pattern with high levels in brain, placenta, spleen, and uterus only. Both alpha subunits exist as multiple transcripts whereas beta(1) exists as a single message. This study reports for the first time the tissue distribution of human sGC message and demonstrates that sGC isoforms are nonuniformly expressed which may be useful if the enzyme is to be exploited as a therapeutic target.