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Bioorg Med Chem Lett. 2012 Mar 1;22(5):1980-4. doi: 10.1016/j.bmcl.2012.01.031. Epub 2012 Jan 21.

3,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase (nNOS) inhibitors.

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NeurAxon Inc., 2395 Speakman Drive, Suite #1001, Mississauga, ON, Canada L5K 1B3.


A series of 3,5-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). Various guanidine isosteric groups were explored at the 5-position of the indole ring, while keeping the basic amine side chain such as N-methylpiperidine ring, fixed at the 3-position of the indole ring. Compounds having 2-thiophene amidine and 2-furanyl amidine groups (7, 8, 10 and 12) showed increased activity for human neuronal NOS and good selectivity over endothelial and inducible NOS isoforms. Compound 8 was shown to reverse (10mg/kg, ip) thermal hyperalgesia in the L(5)/L(6) spinal nerve ligation (neuropathic pain) model and was devoid of any significant drug-drug interaction potential due to cytochrome P450 inhibition or cardiovascular liabilities associated with the inhibition of endothelial NOS.

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