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

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

doi:10.1016/j.bmcl.2011.07.042

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

Shawn Maddaford, Paul Renton, Joanne Speed, Subhash C. Annedi, Jailall Ramnauth, Suman Rakhit, John Andrews, Gabriela Mladenova, Lisa Majuta, Frank Porreca

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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.

Original language	English (US)
Pages (from-to)	5234-5238
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2011.07.042
State	Published - Sep 15 2011

Keywords

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

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2011.07.042

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title = "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.",

keywords = "1,6-Disubstitued indole derivatives, Nitric oxide, Nitric oxide synthase, Nitric oxide synthase inhibitors, Selective neuronal nitric oxide synthase inhibitors",

author = "Shawn Maddaford and Paul Renton and Joanne Speed and Annedi, {Subhash C.} and Jailall Ramnauth and Suman Rakhit and John Andrews and Gabriela Mladenova and Lisa Majuta and Frank Porreca",

note = "Funding Information: We are grateful to NoAb BioDiscoveries Inc. (Mississauga, ON, Canada) and Asinex Ltd (Moscow, Russia) for performing the human NOS inhibition assays. We thank the Natural Sciences and Engineering Research Council (NSERC) of Canada for providing an Industrial Research Fellowship to GM. ",

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doi = "10.1016/j.bmcl.2011.07.042",

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AU - Maddaford, Shawn

AU - Renton, Paul

AU - Speed, Joanne

AU - Annedi, Subhash C.

AU - Ramnauth, Jailall

AU - Rakhit, Suman

AU - Andrews, John

AU - Mladenova, Gabriela

AU - Majuta, Lisa

AU - Porreca, Frank

N1 - Funding Information: We are grateful to NoAb BioDiscoveries Inc. (Mississauga, ON, Canada) and Asinex Ltd (Moscow, Russia) for performing the human NOS inhibition assays. We thank the Natural Sciences and Engineering Research Council (NSERC) of Canada for providing an Industrial Research Fellowship to GM.

PY - 2011/9/15

Y1 - 2011/9/15

N2 - 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.

AB - 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.

KW - 1,6-Disubstitued indole derivatives

KW - Nitric oxide

KW - Nitric oxide synthase

KW - Nitric oxide synthase inhibitors

KW - Selective neuronal nitric oxide synthase inhibitors

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

Abstract

Keywords

ASJC Scopus subject areas

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