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

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

21 Citations (Scopus)

17 Downloads (Pure)

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 Sept 2016

Bibliographical note

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

Keywords

cannabinoid
negative allosteric modulator
CB1NAM
indole sulfonamide

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Accepted Manuscript
© 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
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

SN - 0960-894X

VL - 26

SP - 4403

EP - 4407

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 18

ER -

Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators

Abstract

Bibliographical note

Keywords

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Iain Greig

Laurent Trembleau

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