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

Abstract

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 (30 mg/kg) in an in vivo rat model of dural inflammation relevant to migraine pain.

• Authors: Shawn Maddaford, Paul Renton, Joanne Speed, Subhash C Annedi, Jailall Ramnauth, Suman Rakhit, John Andrews, Gabriela Mladenova, Lisa Majuta, Frank Porreca
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 18 Pg. 5234-8 (Sep 15 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21824773 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Indoles
• Nitric Oxide Synthase

Topics

• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Indoles (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Nitric Oxide Synthase (antagonists & inhibitors, metabolism)
• Stereoisomerism
• Structure-Activity Relationship