Synthesis and biological evaluation of novel pyrazoles and indazoles as activators of the nitric oxide receptor, soluble guanylate cyclase.
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.
Selwood
D L
DL
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
Brummell
D G
DG
Budworth
J
J
Burtin
G E
GE
Campbell
R O
RO
Chana
S S
SS
Charles
I G
IG
Fernandez
P A
PA
Glen
R C
RC
Goggin
M C
MC
Hobbs
A J
AJ
Kling
M R
MR
Liu
Q
Q
Madge
D J
DJ
Meillerais
S
S
Powell
K L
KL
Reynolds
K
K
Spacey
G D
GD
Stables
J N
JN
Tatlock
M A
MA
Wheeler
K A
KA
Wishart
G
G
Woo
C K
CK
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
D007191:Indazoles; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D009569:Nitric Oxide; D006162:Guanylate Cyclase; C419404:CFM 1571