The Pentafluorosulfanyl Group in Cannabinoid Receptor Ligands: Synthesis and Comparison with Trifluoromethyl and tert-Butyl Analogues

Stefano Altomonte, Gemma L. Baillie, Ruth A. Ross, Jennifer Riley, Matteo Zanda

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

An array of cannabinoid ligands, bearing meta- and para-substituted pentafluorosulfanyl (SF5) aniline groups in position 3 of the pyrazole ring, was efficiently synthesised and compared with the exact trifluoromethyl and tert-butyl analogues. In general, the SF5 substituted ligands showed higher lipophilicity (i.e. log P values) than the CF3 counterparts and lower lipophilicity than the tert-butyl ones. In terms of pharmacological activity, SF5 pyrazoles generally showed slightly higher or equivalent CB1 receptor affinity (Ki), always in the nanomolar range, and selectivity towards the CB2 relative to both CF3 and tert-butyl analogues. Functional β-arrestin recruitment assays were used to determine equilibrium dissociation constants (Kb) and showed that all of the tested SF5 and CF3 compounds are CB1 neutral antagonists. These results confirm the possibility of successfully using an aromatic SF5 group as a stable, synthetically accessible and effective bioisosteric analogue of the electron-withdrawing CF3 group, and possibly also of bulky aliphatic groups, for drug discovery and development applications.
Original languageEnglish
Pages (from-to)20164-20176
Number of pages13
JournalRSC Advances
Volume4
Issue number39
Early online date15 Apr 2014
DOIs
Publication statusPublished - 2014

Fingerprint

Cannabinoid Receptors
Bearings (structural)
Ligands
Pyrazoles
Arrestin
Cannabinoid Receptor CB1
Cannabinoids
Aniline
Assays
Electrons
pyrazole
Drug Discovery
aniline

Cite this

The Pentafluorosulfanyl Group in Cannabinoid Receptor Ligands : Synthesis and Comparison with Trifluoromethyl and tert-Butyl Analogues. / Altomonte, Stefano; Baillie, Gemma L.; Ross, Ruth A.; Riley, Jennifer; Zanda, Matteo.

In: RSC Advances, Vol. 4, No. 39, 2014, p. 20164-20176.

Research output: Contribution to journalArticle

Altomonte, Stefano ; Baillie, Gemma L. ; Ross, Ruth A. ; Riley, Jennifer ; Zanda, Matteo. / The Pentafluorosulfanyl Group in Cannabinoid Receptor Ligands : Synthesis and Comparison with Trifluoromethyl and tert-Butyl Analogues. In: RSC Advances. 2014 ; Vol. 4, No. 39. pp. 20164-20176.
@article{ccf2fa5177474b759445c4a21c58bdf0,
title = "The Pentafluorosulfanyl Group in Cannabinoid Receptor Ligands: Synthesis and Comparison with Trifluoromethyl and tert-Butyl Analogues",
abstract = "An array of cannabinoid ligands, bearing meta- and para-substituted pentafluorosulfanyl (SF5) aniline groups in position 3 of the pyrazole ring, was efficiently synthesised and compared with the exact trifluoromethyl and tert-butyl analogues. In general, the SF5 substituted ligands showed higher lipophilicity (i.e. log P values) than the CF3 counterparts and lower lipophilicity than the tert-butyl ones. In terms of pharmacological activity, SF5 pyrazoles generally showed slightly higher or equivalent CB1 receptor affinity (Ki), always in the nanomolar range, and selectivity towards the CB2 relative to both CF3 and tert-butyl analogues. Functional β-arrestin recruitment assays were used to determine equilibrium dissociation constants (Kb) and showed that all of the tested SF5 and CF3 compounds are CB1 neutral antagonists. These results confirm the possibility of successfully using an aromatic SF5 group as a stable, synthetically accessible and effective bioisosteric analogue of the electron-withdrawing CF3 group, and possibly also of bulky aliphatic groups, for drug discovery and development applications.",
author = "Stefano Altomonte and Baillie, {Gemma L.} and Ross, {Ruth A.} and Jennifer Riley and Matteo Zanda",
year = "2014",
doi = "10.1039/C4RA01212G",
language = "English",
volume = "4",
pages = "20164--20176",
journal = "RSC Advances",
issn = "2046-2069",
publisher = "Royal Society of Chemistry",
number = "39",

}

TY - JOUR

T1 - The Pentafluorosulfanyl Group in Cannabinoid Receptor Ligands

T2 - Synthesis and Comparison with Trifluoromethyl and tert-Butyl Analogues

AU - Altomonte, Stefano

AU - Baillie, Gemma L.

AU - Ross, Ruth A.

AU - Riley, Jennifer

AU - Zanda, Matteo

PY - 2014

Y1 - 2014

N2 - An array of cannabinoid ligands, bearing meta- and para-substituted pentafluorosulfanyl (SF5) aniline groups in position 3 of the pyrazole ring, was efficiently synthesised and compared with the exact trifluoromethyl and tert-butyl analogues. In general, the SF5 substituted ligands showed higher lipophilicity (i.e. log P values) than the CF3 counterparts and lower lipophilicity than the tert-butyl ones. In terms of pharmacological activity, SF5 pyrazoles generally showed slightly higher or equivalent CB1 receptor affinity (Ki), always in the nanomolar range, and selectivity towards the CB2 relative to both CF3 and tert-butyl analogues. Functional β-arrestin recruitment assays were used to determine equilibrium dissociation constants (Kb) and showed that all of the tested SF5 and CF3 compounds are CB1 neutral antagonists. These results confirm the possibility of successfully using an aromatic SF5 group as a stable, synthetically accessible and effective bioisosteric analogue of the electron-withdrawing CF3 group, and possibly also of bulky aliphatic groups, for drug discovery and development applications.

AB - An array of cannabinoid ligands, bearing meta- and para-substituted pentafluorosulfanyl (SF5) aniline groups in position 3 of the pyrazole ring, was efficiently synthesised and compared with the exact trifluoromethyl and tert-butyl analogues. In general, the SF5 substituted ligands showed higher lipophilicity (i.e. log P values) than the CF3 counterparts and lower lipophilicity than the tert-butyl ones. In terms of pharmacological activity, SF5 pyrazoles generally showed slightly higher or equivalent CB1 receptor affinity (Ki), always in the nanomolar range, and selectivity towards the CB2 relative to both CF3 and tert-butyl analogues. Functional β-arrestin recruitment assays were used to determine equilibrium dissociation constants (Kb) and showed that all of the tested SF5 and CF3 compounds are CB1 neutral antagonists. These results confirm the possibility of successfully using an aromatic SF5 group as a stable, synthetically accessible and effective bioisosteric analogue of the electron-withdrawing CF3 group, and possibly also of bulky aliphatic groups, for drug discovery and development applications.

U2 - 10.1039/C4RA01212G

DO - 10.1039/C4RA01212G

M3 - Article

VL - 4

SP - 20164

EP - 20176

JO - RSC Advances

JF - RSC Advances

SN - 2046-2069

IS - 39

ER -