Tricyclic Fused Pyrazoles with a ‘Click’ 1,2,3-Triazole Substituent in Position 3 Are Nanomolar CB1 Receptor Ligands

Chiara Zanato; Maria Grazia Cascio; Paolo Lazzari; Roger Pertwee; Andrea Testa; Matteo Zanda

doi:10.1055/s-0034-1379887

Synthesis, Table of Contents

Synthesis 2015; 47(06): 817-826
DOI: 10.1055/s-0034-1379887

paper

Tricyclic Fused Pyrazoles with a ‘Click’ 1,2,3-Triazole Substituent in Position 3 Are Nanomolar CB₁ Receptor Ligands

Chiara Zanato

^aKosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Scotland, UK Email: m.zanda@abdn.ac.uk

,

Maria Grazia Cascio

^aKosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Scotland, UK Email: m.zanda@abdn.ac.uk

,

Paolo Lazzari*

^bPharmaNess Scarl, Parco Scientifico della Sardegna, Edificio 5, Loc. Piscinamanna, 09010 Pula (CA), Italy

^cKemoTech s.r.l., Parco Scientifico della Sardegna, Edificio 3, Loc. Piscinamanna, 09010 Pula (CA), Italy

,

Roger Pertwee

^aKosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Scotland, UK Email: m.zanda@abdn.ac.uk

,

Andrea Testa

^aKosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Scotland, UK Email: m.zanda@abdn.ac.uk

,

Matteo Zanda*

^aKosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Scotland, UK Email: m.zanda@abdn.ac.uk

^dC.N.R.-I.C.R.M., via Mancinelli 7, 20131 Milano, Italy

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Abstract

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Abstract

Structural modification of the potent conformationally constrained tricyclic pyrazole CB₁ ligand NESS0327 was achieved by replacing: (1) the chlorine substituent on the tricycle with a 3-fluoropropyl chain, and (2) the pyrazole 3-{[(piperidino)amino]carbonyl} substituent with a 4-substituted 1,2,3-triazole group obtained by click chemistry from an alkynyl precursor. Among the resulting compounds, two are particularly promising candidates for [¹⁸F]radiolabelling and PET imaging studies of the CB₁ receptor, as they displayed K _i CB₁ = 62.5 nM and 42.5 nM, respectively, in the same range as that displayed by rimonabant.

Key words

cannabinoids - PET imaging - fluorine - Sonogashira reaction - click chemistry

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References

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