4-Cyano-5-(2-Thiophenyl)-Pyrazoles are High Affinity CB1 Receptor Ligands

Stefano Altomonte; Gemma Louise Baillie; Ruth Ross; Matteo Zanda

doi:10.1039/C4RA17274D

4-Cyano-5-(2-Thiophenyl)-Pyrazoles are High Affinity CB1 Receptor Ligands

Stefano Altomonte, Gemma Louise Baillie, Ruth Ross, Matteo Zanda

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

7 Citations (Scopus)

Abstract

Pyrazoles bearing a 5-thiophenyl and a 4-cyano group were synthesised and tested for their affinity to the cannabinoid CB1 receptor showing in many cases single digit nanomolar Ki values and moderate to good selectivity towards the CB2 receptor. Some of these pyrazole ligands, such as 8g, displayed relatively low lipophilicity (experimental logP < 4) and high calculated Topological Polar Surface Area (TPSA) (>90) suggesting that these compounds may behave as peripherally restricted CB1 ligands. Furthermore, 2-fluoroethyl carboxamides 8d, 8h and 8l are interesting candidates for further development into PET tracers.

Original language	English
Pages (from-to)	13692-13701
Number of pages	10
Journal	RSC Advances
Volume	5
Issue number	18
Early online date	21 Jan 2015
DOIs	https://doi.org/10.1039/C4RA17274D
Publication status	Published - 2015

Keywords

4-Cyano-5-(2-thiophenyl)-pyrazoles
CB1 receptor ligands
Cannabinoid receptors
CB1 receptor
CB1 ligands

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@article{1d18aa3179784a939b0024046d3e7975,

title = "4-Cyano-5-(2-Thiophenyl)-Pyrazoles are High Affinity CB1 Receptor Ligands",

abstract = "Pyrazoles bearing a 5-thiophenyl and a 4-cyano group were synthesised and tested for their affinity to the cannabinoid CB1 receptor showing in many cases single digit nanomolar Ki values and moderate to good selectivity towards the CB2 receptor. Some of these pyrazole ligands, such as 8g, displayed relatively low lipophilicity (experimental logP < 4) and high calculated Topological Polar Surface Area (TPSA) (>90) suggesting that these compounds may behave as peripherally restricted CB1 ligands. Furthermore, 2-fluoroethyl carboxamides 8d, 8h and 8l are interesting candidates for further development into PET tracers.",

keywords = "4-Cyano-5-(2-thiophenyl)-pyrazoles , CB1 receptor ligands , Cannabinoid receptors , CB1 receptor , CB1 ligands",

author = "Stefano Altomonte and Baillie, {Gemma Louise} and Ruth Ross and Matteo Zanda",

note = "Acknowledgements We thank the European Commission for financial support (Industry Academia Partnerships and Pathways project “PET BRAIN”, Contract no 251482). The EPSRC National Mass Spectrometry Service Centre (Swansea, UK) is gratefully acknowledged for performing HRMS analyses. S.A. thanks the Northern Research Partnership (http://www.northscotland-research.ac.uk/) and Pharmaness (http://www.pharmaness.it) for co-funding a PhD studentship.",

year = "2015",

doi = "10.1039/C4RA17274D",

language = "English",

volume = "5",

pages = "13692--13701",

journal = "RSC Advances",

issn = "2046-2069",

publisher = "Royal Society of Chemistry",

number = "18",

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T1 - 4-Cyano-5-(2-Thiophenyl)-Pyrazoles are High Affinity CB1 Receptor Ligands

AU - Altomonte, Stefano

AU - Baillie, Gemma Louise

AU - Ross, Ruth

AU - Zanda, Matteo

N1 - Acknowledgements We thank the European Commission for financial support (Industry Academia Partnerships and Pathways project “PET BRAIN”, Contract no 251482). The EPSRC National Mass Spectrometry Service Centre (Swansea, UK) is gratefully acknowledged for performing HRMS analyses. S.A. thanks the Northern Research Partnership (http://www.northscotland-research.ac.uk/) and Pharmaness (http://www.pharmaness.it) for co-funding a PhD studentship.

PY - 2015

Y1 - 2015

N2 - Pyrazoles bearing a 5-thiophenyl and a 4-cyano group were synthesised and tested for their affinity to the cannabinoid CB1 receptor showing in many cases single digit nanomolar Ki values and moderate to good selectivity towards the CB2 receptor. Some of these pyrazole ligands, such as 8g, displayed relatively low lipophilicity (experimental logP < 4) and high calculated Topological Polar Surface Area (TPSA) (>90) suggesting that these compounds may behave as peripherally restricted CB1 ligands. Furthermore, 2-fluoroethyl carboxamides 8d, 8h and 8l are interesting candidates for further development into PET tracers.

AB - Pyrazoles bearing a 5-thiophenyl and a 4-cyano group were synthesised and tested for their affinity to the cannabinoid CB1 receptor showing in many cases single digit nanomolar Ki values and moderate to good selectivity towards the CB2 receptor. Some of these pyrazole ligands, such as 8g, displayed relatively low lipophilicity (experimental logP < 4) and high calculated Topological Polar Surface Area (TPSA) (>90) suggesting that these compounds may behave as peripherally restricted CB1 ligands. Furthermore, 2-fluoroethyl carboxamides 8d, 8h and 8l are interesting candidates for further development into PET tracers.

KW - 4-Cyano-5-(2-thiophenyl)-pyrazoles

KW - CB1 receptor ligands

KW - Cannabinoid receptors

KW - CB1 receptor

KW - CB1 ligands

U2 - 10.1039/C4RA17274D

DO - 10.1039/C4RA17274D

M3 - Article

VL - 5

SP - 13692

EP - 13701

JO - RSC Advances

JF - RSC Advances

SN - 2046-2069

IS - 18

ER -

4-Cyano-5-(2-Thiophenyl)-Pyrazoles are High Affinity CB1 Receptor Ligands

Abstract

Keywords

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