4-Substituted indazoles as new inhibitors of neuronal nitric oxide synthase

• Published in: Bioorganic & medicinal chemistry letters 2007-06, Vol.17 (11), p.3177-3180
• Main Authors: Boulouard, Michel, Schumann-Bard, Pascale, Butt-Gueulle, Sabrina, Lohou, Elodie, Stiebing, Silvia, Collot, Valérie, Rault, Sylvain
• Format: Article
• Language: English
• Subjects: Analgesics; Animals; Antinociceptive; Biological and medical sciences; Bromine - chemistry; Cerebellum - cytology; Cerebellum - drug effects; Cerebellum - enzymology; Cognitive science; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Indazole; Indazoles - chemical synthesis; Indazoles - chemistry; Indazoles - pharmacology; Inhibitor; Medical sciences; Neuronal nitric oxide synthase; Neurons - drug effects; Neurons - enzymology; Neuropharmacology; Neuroscience; Nitric oxide; Nitric Oxide Synthase Type I - antagonists & inhibitors; Pharmacology. Drug treatments; Rats; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.03.024

The synthesis and in vitro and in vivo pharmacological evaluation of a complete series of substituted indazoles as new inhibitors of nNOS are reported. A series of halo-1- H-indazoles has been synthesized and evaluated for its inhibitory activity on neuronal nitric oxide synthase. Introduction of bromine at the C4 position of the indazole ring system provided a compound almost as potent as the reference compound, that is, 7-nitroindazole (7-NI). The importance of position 4 is further demonstrated by the synthesis and pharmacological evaluation of the 4-nitroindazole which was also a potent inhibitor of NOS activity. These compounds also exhibited in vivo NOS inhibitory activity, as attested by potent antinociceptive effects following systemic administration.