1,6-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 18; pp. 5234 - 5238
• Main Authors: Maddaford, Shawn, Renton, Paul, Speed, Joanne, Annedi, Subhash C., Ramnauth, Jailall, Rakhit, Suman, Andrews, John, Mladenova, Gabriela, Majuta, Lisa, Porreca, Frank
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-09-2011; Elsevier
• Subjects: 1,6-Disubstitued indole derivatives; Analgesics; animal models; Biological and medical sciences; Dose-Response Relationship, Drug; endothelial nitric oxide synthase; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; inducible nitric oxide synthase; inflammation; Medical sciences; migraine; Molecular Structure; neuronal nitric oxide synthase; Neuropharmacology; Nitric oxide; Nitric oxide synthase; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Nitric oxide synthase inhibitors; oral administration; pain; Pharmacology. Drug treatments; Selective neuronal nitric oxide synthase inhibitors; Stereoisomerism; Structure-Activity Relationship; Nitric oxide synthase; 1,6-Disubstitued indole derivatives; Nitric oxide synthase inhibitors; Selective neuronal nitric oxide synthase inhibitors; Nitric oxide; inhibitors; Five membered ring; Rat; Nitrogen heterocycle; Nitric oxide synthase inhibitor; Isozyme; Central nervous system; Selectivity; Pyrrolidine derivatives; Structure activity relation; Bicyclic compound; Aromatic compound; Chemical synthesis; Human; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; In vitro; Nitric-oxide synthase; In vivo; Vertebrata; Amidine; Sulfur heterocycle; Mammalia; Analgesic; Animal; Selective neuronal nitric oxide synthase; Oxidoreductases; Indole derivatives
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.07.042

A series of 1,6-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). By varying the basic amine side chain at the 1-position of the indole ring, several potent and selective inhibitors of human neuronal NOS were identified. In general compounds with bulkier side chains displayed increased selectivity for nNOS over eNOS and iNOS isoforms. One of the compounds, (R)-8 was shown to reduce tactile hyperesthesia (allodynia) after oral administration (30mg/kg) in an in vivo rat model of dural inflammation relevant to migraine pain.