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

作者：Maddaford Shawn; Renton Paul; Speed Joanne; Annedi Subhash C^*; Ramnauth Jailall; Rakhit Suman; Andrews John; Mladenova Gabriela; Majuta Lisa; Porreca Frank

来源：Bioorganic & Medicinal Chemistry Letters, 2011, 21(18): 5234-5238.

DOI：10.1016/j.bmcl.2011.07.042

• 1,6-Disubstitued indole derivatives
• Nitric oxide
• Nitric oxide synthase
• Nitric oxide synthase inhibitors
• Selective neuronal nitric oxide synthase inhibitors

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.

• 出版日期2011-9-15