Design, Synthesis, and Biological Evaluation of 3,4-Dihydroquinolin-2(1H)-one and 1,2,3,4-Tetrahydroquinoline-Based Selective Human Neuronal Nitric Oxide Synthase (nNOS) Inhibitors
| Autor: | Frank Porreca, Subhash C. Annedi, Peter Dove, David H. Lee, Milena De Felice, Gabriela Mladenova, Salvatore Zinghini, Joanne Speed, Concettina Catalano, Jailall Ramnauth, Sheela Nair, Shawn Maddaford, John S. Andrews, Paul Renton, Sarah Silverman, Suman Rakhit |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Stereochemistry Migraine Disorders Nitric Oxide Synthase Type I Pharmacology Article Rats Sprague-Dawley Amidine Structure-Activity Relationship chemistry.chemical_compound Oral administration Drug Discovery medicine Thiophene Animals Humans Potency biology Chemistry Rats Nitric oxide synthase Allodynia Hyperalgesia Neuropathic pain Quinolines biology.protein Neuralgia Molecular Medicine medicine.symptom Neuronal Nitric Oxide Synthase |
| Zdroj: | Journal of Medicinal Chemistry. 54:5562-5575 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm200648s |
| Popis: | Neuronal nitric oxide synthase (nNOS) inhibitors are effective in preclinical models of many neurological disorders. In this study, two related series of compounds, 3,4-dihydroquinolin-2(1H)-one and 1,2,3,4-tetrahydroquinoline, containing a 6-substituted thiophene amidine group were synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). A structure-activity relationship (SAR) study led to the identification of a number of potent and selective nNOS inhibitors. Furthermore, a few representative compounds were shown to possess druglike properties, features that are often difficult to achieve when designing nNOS inhibitors. Compound (S)-35, with excellent potency and selectivity for nNOS, was shown to fully reverse thermal hyperalgesia when given to rats at a dose of 30 mg/kg intraperitonieally (ip) in the L5/L6 spinal nerve ligation model of neuropathic pain (Chung model). In addition, this compound reduced tactile hyperesthesia (allodynia) after oral administration (30 mg/kg) in a rat model of dural inflammation relevant to migraine pain. |
| Databáze: | OpenAIRE |
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