| Literature DB >> 11141091 |
D L Selwood1, D G Brummell, J Budworth, G E Burtin, R O Campbell, S S Chana, I G Charles, P A Fernandez, R C Glen, M C Goggin, A J Hobbs, M R Kling, Q Liu, D J Madge, S Meillerais, K L Powell, K Reynolds, G D Spacey, J N Stables, M A Tatlock, K A Wheeler, G Wishart, C K Woo.
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.Entities:
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Year: 2001 PMID： 11141091 DOI： 10.1021/jm001034k
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446