Novel, druglike 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine-based selective inhibitors of human neuronal nitric oxide synthase (nNOS) |
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Authors: | Annedi Subhash C Ramnauth Jailall Cossette Michele Maddaford Shawn P Dove Peter Rakhit Suman Andrews John S Porreca Frank |
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Institution: | NeurAxon Inc., 2395 Speakman Drive, Suite # 1001, Mississauga, ON, Canada L5K 1B3. sannedi@neuraxon.com |
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Abstract: | A novel class of 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzob]azepine derivatives was designed, synthesized and evaluated as human nitric oxide synthase (NOS) inhibitors. Structure-activity relationship studies based on various basic amine side chains attached at the 1-position of the 2,3,4,5-tetrahydro-1H-benzob]azepine ring led to the identification of several potent and highly selective inhibitors (17, 18, 25, (±)-39, and (±)-40) of human neuronal NOS. The potential therapeutic application of one of these new selective nNOS inhibitors (17) was demonstrated in an in vivo spinal nerve ligation model of neuropathic pain, and various in vitro safety pharmacology studies such as the hERG K(+) channel inhibition assay and high throughput broad screen (minimal activity at 79 receptors/transporters/ion channels). |
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