title: 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.
authors.affiliation: Biological & Medicinal Chemistry and Molecular & Cellular Biology, The Wolfson Institute for Biomedical Research, University College London, The Cruciform Building, Gower Street, London WC1E 6BT, UK. d.selwood@ucl.ac.uk
authors.forename: D L
authors.initials: DL
authors.lastname: Selwood
authors.forename: D G
authors.initials: DG
authors.lastname: Brummell
authors.forename: J
authors.initials: J
authors.lastname: Budworth
authors.forename: G E
authors.initials: GE
authors.lastname: Burtin
authors.forename: R O
authors.initials: RO
authors.lastname: Campbell
authors.forename: S S
authors.initials: SS
authors.lastname: Chana
authors.forename: I G
authors.initials: IG
authors.lastname: Charles
authors.forename: P A
authors.initials: PA
authors.lastname: Fernandez
authors.forename: R C
authors.initials: RC
authors.lastname: Glen
authors.forename: M C
authors.initials: MC
authors.lastname: Goggin
authors.forename: A J
authors.initials: AJ
authors.lastname: Hobbs
authors.forename: M R
authors.initials: MR
authors.lastname: Kling
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: D J
authors.initials: DJ
authors.lastname: Madge
authors.forename: S
authors.initials: S
authors.lastname: Meillerais
authors.forename: K L
authors.initials: KL
authors.lastname: Powell
authors.forename: K
authors.initials: K
authors.lastname: Reynolds
authors.forename: G D
authors.initials: GD
authors.lastname: Spacey
authors.forename: J N
authors.initials: JN
authors.lastname: Stables
authors.forename: M A
authors.initials: MA
authors.lastname: Tatlock
authors.forename: K A
authors.initials: KA
authors.lastname: Wheeler
authors.forename: G
authors.initials: G
authors.lastname: Wishart
authors.forename: C K
authors.initials: CK
authors.lastname: Woo
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D007191:Indazoles; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D009569:Nitric Oxide; D006162:Guanylate Cyclase; C419404:CFM 1571