Synthesis and Biological Evaluation of Novel Pyrazoles and Indazoles as Activators of the Nitric Oxide Receptor, Soluble Guanylate Cyclase

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.

Cardiovascular Effects of Modulators of Soluble Guanylyl Cyclase Activity

“…Another effort at compound screening resulted in the development of CFM1571 and a couple of related substances [229]. All of these are benzydamine analogs and are thus structurally related to YC-1.…”

Synthesis, Nematicidal and Antifungal Properties of Hybrid Heterocyclics

“…Some aryl pyrazoles were reported to be non-nucleoside human immunodeficiency virus (HIV-1) reverse transcriptase inhibitor, 24 COX-2 inhibitor, [25][26][27] activator of the nitric oxide receptor and to have soluble guanylate cyclase activity. 28 Nematodes are tiny worms, some of them are plant parasites, and can play an important role in the predisposition of the host plant to the invansion by secondary pathogens. 29 Plants attacked by nematodes show retarded growth and development, as well as loss in the quality and quantity of the harvest.…”

Activated fly ash-catalyzed synthesis of naphthyl-substituted cyclohexenone carboxylates, indazolonols, and nitro hydrazones in “dry media”

“…A wide range of structurally diverse indazole nuclei have aroused enormous interest in the recent years due to their wide variety of pharmacological activities such as antimicrobial activity (1), inhibitors of protein kinase B/Akt (2), leishmanocidal activity (3), antiprotozoal agents (3), antichagasic activity (3), trypanocidal activity (3), inhibitors of S-adenosylhomocysteine/methylthio adenosine nucleosides (4), inhibition of platelet aggregation (5), and potent activator of the nitric oxide receptor (5). The indazole nucleus is a widely studied biological scaffold that has emerged as a core structural unit of a variety of bioactive molecules (6Á10).…”