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

Selwood, DL; Brummell, DG; Budworth, J; Burtin, GE; Campbell, RO; Chana, SS; Charles, IG; Fernandez, PA; Glen, RC; Goggin, MC; Hobbs, AJ; Kling, MR; Liu, Q; Madge, DJ; Meillerais, S; Powell, KL; Reynolds, K; Spacey, GD; Stables, JN; Tatlock, MA; Wheeler, KA; Wishart, G; Woo, CK

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

Selwood, DL Brummell, DG Budworth, J Burtin, GE Campbell, RO Chana, SS Charles, IG Fernandez, PA Glen, RC Goggin, MC Hobbs, AJ Kling, MR Liu, Q Madge, DJ Meillerais, S Powell, KL Reynolds, K Spacey, GD Stables, JN Tatlock, MA Wheeler, KA Wishart, G Woo, CK

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Publication Type:: Journal Article
Citation:: J Med Chem, 2001, 44 (1), pp. 78 - 93
Issue Date:: 2001-01-04

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Field	Value	Language
dc.contributor.author	Selwood, DL	en_US
dc.contributor.author	Brummell, DG	en_US
dc.contributor.author	Budworth, J	en_US
dc.contributor.author	Burtin, GE	en_US
dc.contributor.author	Campbell, RO	en_US
dc.contributor.author	Chana, SS	en_US
dc.contributor.author	Charles, IG	en_US
dc.contributor.author	Fernandez, PA	en_US
dc.contributor.author	Glen, RC	en_US
dc.contributor.author	Goggin, MC	en_US
dc.contributor.author	Hobbs, AJ	en_US
dc.contributor.author	Kling, MR	en_US
dc.contributor.author	Liu, Q	en_US
dc.contributor.author	Madge, DJ	en_US
dc.contributor.author	Meillerais, S	en_US
dc.contributor.author	Powell, KL	en_US
dc.contributor.author	Reynolds, K	en_US
dc.contributor.author	Spacey, GD	en_US
dc.contributor.author	Stables, JN	en_US
dc.contributor.author	Tatlock, MA	en_US
dc.contributor.author	Wheeler, KA	en_US
dc.contributor.author	Wishart, G	en_US
dc.contributor.author	Woo, CK	en_US
dc.date.issued	2001-01-04	en_US
dc.identifier.citation	J Med Chem, 2001, 44 (1), pp. 78 - 93	en_US
dc.identifier.issn	0022-2623	en_US
dc.identifier.uri	http://hdl.handle.net/10453/13142
dc.description.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.	en_US
dc.language	eng	en_US
dc.relation.ispartof	J Med Chem	en_US
dc.relation.isbasedon	10.1021/jm001034k	en_US
dc.subject.classification	Medicinal & Biomolecular Chemistry	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Rats	en_US
dc.subject.mesh	Rats, Sprague-Dawley	en_US
dc.subject.mesh	Nitric Oxide	en_US
dc.subject.mesh	Pyrazoles	en_US
dc.subject.mesh	Indazoles	en_US
dc.subject.mesh	Guanylate Cyclase	en_US
dc.subject.mesh	Platelet Aggregation Inhibitors	en_US
dc.subject.mesh	Enzyme Activation	en_US
dc.subject.mesh	Structure-Activity Relationship	en_US
dc.subject.mesh	Solubility	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	In Vitro Techniques	en_US
dc.title	Synthesis and biological evaluation of novel pyrazoles and indazoles as activators of the nitric oxide receptor, soluble guanylate cyclase.	en_US
dc.type	Journal Article
utslib.citation.volume	1	en_US
utslib.citation.volume	44	en_US
utslib.location.activity	United States	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
utslib.for	0305 Organic Chemistry	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - ithree - Institute of Infection, Immunity and Innovation
utslib.copyright.status	closed_access
pubs.issue	1	en_US
pubs.publication-status	Published	en_US
pubs.volume	44	en_US

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.

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http://hdl.handle.net/10453/13142