Novel, druglike 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine-based selective inhibitors of human neuronal nitric oxide synthase (nNOS)

Subhash C Annedi; Jailall Ramnauth; Michele Cossette; Shawn P Maddaford; Peter Dove; Suman Rakhit; John S Andrews; Frank Porreca

doi:10.1016/j.bmcl.2012.02.004

Novel, druglike 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine-based selective inhibitors of human neuronal nitric oxide synthase (nNOS)

Bioorg Med Chem Lett. 2012 Apr 1;22(7):2510-3. doi: 10.1016/j.bmcl.2012.02.004. Epub 2012 Feb 9.

Authors

Subhash C Annedi¹, Jailall Ramnauth, Michele Cossette, Shawn P Maddaford, Peter Dove, Suman Rakhit, John S Andrews, Frank Porreca

Affiliation

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

PMID: 22370270
DOI: 10.1016/j.bmcl.2012.02.004

Abstract

A novel class of 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]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-benzo[b]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).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analgesics / administration & dosage
Analgesics / chemical synthesis*
Analgesics / therapeutic use
Animals
Benzazepines / administration & dosage
Benzazepines / chemical synthesis*
Benzazepines / therapeutic use
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / therapeutic use
High-Throughput Screening Assays
Humans
Mice
Neuralgia / drug therapy*
Neuralgia / enzymology
Neuralgia / physiopathology
Nitric Oxide Synthase Type I / antagonists & inhibitors*
Nitric Oxide Synthase Type I / metabolism
Nitric Oxide Synthase Type II / metabolism
Nitric Oxide Synthase Type III / metabolism
Recombinant Proteins / metabolism
Spinal Nerves / drug effects
Spinal Nerves / enzymology
Spinal Nerves / physiopathology
Stereoisomerism
Structure-Activity Relationship

Substances

Analgesics
Benzazepines
Enzyme Inhibitors
Recombinant Proteins
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III