Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators

Iain R. Greig; Gemma L. Baillie; Mostafa Hamed Abdelrahman; Laurent Trembleau; Ruth A. Ross

doi:10.1016/j.bmcl.2016.08.018

Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators

Iain R. Greig, Gemma L. Baillie, Mostafa Hamed Abdelrahman, Laurent Trembleau, Ruth A. Ross

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Abstract

Existing CB1 negative allosteric modulators (NAMs) fall into a limited range of structural classes, for which pharmacokinetic properties have not been reported, but are expected to be sub-optimal. In this study, we show a novel series of indole sulfonamides which have greatly improved metabolic stability and permeability compared to the most widely-studied CB1 PAM (Org27569). Compound 6c (ABD1075) had potency of 3 nM and showed excellent oral exposure and CNS penetration, making it a highly versatile tool for investigating the therapeutic potential of allosteric modulation of the cannabinoid system.
2009 Elsevier Ltd. All rights reserved.

Original language	English
Pages (from-to)	4403-4407
Number of pages	5
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	26
Issue number	18
Early online date	6 Aug 2016
DOIs	https://doi.org/10.1016/j.bmcl.2016.08.018
Publication status	Published - 15 Sep 2016

Keywords

cannabinoid
negative allosteric modulator
CB1NAM
indole sulfonamide

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© 2016 This manuscript version is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by/4.0/
Accepted author manuscript, 467 KBLicence: CC BY

Iain Greig
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Reader
- Institute of Medical Sciences
Person: Academic, Academic Related - Research
Laurent Trembleau
- School of Natural & Computing Sciences, Chemistry - Senior Lecturer
Person: Academic

Cite this

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title = "Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators",

abstract = "Existing CB1 negative allosteric modulators (NAMs) fall into a limited range of structural classes, for which pharmacokinetic properties have not been reported, but are expected to be sub-optimal. In this study, we show a novel series of indole sulfonamides which have greatly improved metabolic stability and permeability compared to the most widely-studied CB1 PAM (Org27569). Compound 6c (ABD1075) had potency of 3 nM and showed excellent oral exposure and CNS penetration, making it a highly versatile tool for investigating the therapeutic potential of allosteric modulation of the cannabinoid system.2009 Elsevier Ltd. All rights reserved.",

keywords = "cannabinoid, negative allosteric modulator, CB1NAM, indole sulfonamide",

author = "Greig, {Iain R.} and Baillie, {Gemma L.} and Abdelrahman, {Mostafa Hamed} and Laurent Trembleau and Ross, {Ruth A.}",

note = "This Letter was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Scottish Universities Life Sciences Alliance (SULSA) in 2011",

year = "2016",

month = sep,

day = "15",

doi = "10.1016/j.bmcl.2016.08.018",

language = "English",

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journal = "Bioorganic & Medicinal Chemistry Letters",

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T1 - Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators

AU - Greig, Iain R.

AU - Baillie, Gemma L.

AU - Abdelrahman, Mostafa Hamed

AU - Trembleau, Laurent

AU - Ross, Ruth A.

N1 - This Letter was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Scottish Universities Life Sciences Alliance (SULSA) in 2011

PY - 2016/9/15

Y1 - 2016/9/15

N2 - Existing CB1 negative allosteric modulators (NAMs) fall into a limited range of structural classes, for which pharmacokinetic properties have not been reported, but are expected to be sub-optimal. In this study, we show a novel series of indole sulfonamides which have greatly improved metabolic stability and permeability compared to the most widely-studied CB1 PAM (Org27569). Compound 6c (ABD1075) had potency of 3 nM and showed excellent oral exposure and CNS penetration, making it a highly versatile tool for investigating the therapeutic potential of allosteric modulation of the cannabinoid system.2009 Elsevier Ltd. All rights reserved.

AB - Existing CB1 negative allosteric modulators (NAMs) fall into a limited range of structural classes, for which pharmacokinetic properties have not been reported, but are expected to be sub-optimal. In this study, we show a novel series of indole sulfonamides which have greatly improved metabolic stability and permeability compared to the most widely-studied CB1 PAM (Org27569). Compound 6c (ABD1075) had potency of 3 nM and showed excellent oral exposure and CNS penetration, making it a highly versatile tool for investigating the therapeutic potential of allosteric modulation of the cannabinoid system.2009 Elsevier Ltd. All rights reserved.

KW - cannabinoid

KW - negative allosteric modulator

KW - CB1NAM

KW - indole sulfonamide

U2 - 10.1016/j.bmcl.2016.08.018

DO - 10.1016/j.bmcl.2016.08.018

M3 - Article

VL - 26

SP - 4403

EP - 4407

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

SN - 0960-894X

IS - 18

ER -

Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators

Abstract

Keywords

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Iain Greig

Laurent Trembleau

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