The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB1 Receptor Positive Allosteric Modulators (PAMs)

Chih-Chung Tseng; Gemma Baillie; Giulia Donvito; Mohammed A. Mustafa; Sophie E. Juola; Chiara Zanato; Chiara Massarenti; Sergio Dall'angelo; William T. A. Harrison; Aron H. Lichtman; Ruth A. Ross; Matteo Zanda; Iain R. Greig

doi:10.1021/acs.jmedchem.9b00252

The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB1 Receptor Positive Allosteric Modulators (PAMs)

Chih-Chung Tseng, Gemma Baillie, Giulia Donvito, Mohammed A. Mustafa, Sophie E. Juola, Chiara Zanato, Chiara Massarenti, Sergio Dall'angelo, William T. A. Harrison, Aron H. Lichtman, Ruth A. Ross, Matteo Zanda^* (Corresponding Author), Iain R. Greig^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

The first generation of CB1 positive allosteric modulators (PAMs; e.g., ZCZ011) featured a 3-indolyl-nitromethane structure. Although a small number of drugs include the nitro group, it is generally not regarded as being “drug-like”, and this is particularly true for aliphatic nitro groups. There are very few case studies where an appropriate bioisostere replaced a nitro group that had a direct role in binding. This may be indicative of the difficulty of replicating its binding interactions. Herein we report the design and synthesis of ligands targeting the allosteric binding site on the CB1 cannabinoid receptor, in which a CF3 group successfully replaced the aliphatic NO2. In general, the CF3-bearing compounds were more potent than their NO2 equivalents and also showed improved in vitro metabolic stability. The CF3-analogue (1) with the best balance of properties was selected for further pharmacological evaluation. Pilot in vivo studies showed that (±)-1 has similar activity to (±)-ZCZ011, with both showing promising efficacy in a mouse model of neuropathic pain.

Original language	English
Pages (from-to)	5049-5062
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	10
Early online date	3 May 2019
DOIs	https://doi.org/10.1021/acs.jmedchem.9b00252
Publication status	Published - 2019

Bibliographical note

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b00252.

Experimental procedures, characterization of all intermediates and target compounds, and copies of NMR spectra of compounds 1, 39-57. Molecular formula strings of target compounds are available.

ACKNOWLEDGEMENTS.
We gratefully thank Signal Pharma and the Canadian Institutes of Health Research Proof of Principle grants PPP-125784 and PP2-139101 for financial support and fellowship (C.C.T), NIH grants R01DA039942, P30DA033934 and VCU School of Pharmacy start-up funds (A.H.L.). We thank the EPSRC National Crystallography Service (University of Southampton) for the X-ray data collection. We are grateful to Dr Monica Sani (CNR-ICRM, Milan, Italy) and Mr Massimo Frigerio (Politecnico di Milano, Italy) for the synthesis of two tetrazole-substituted indoles (Het-1 and Het-2)

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Accepted Manuscript
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00252.
Accepted author manuscript, 483 KBLicence: Unspecified

Cite this

Tseng, C.-C., Baillie, G., Donvito, G., Mustafa, M. A., Juola, S. E., Zanato, C., Massarenti, C., Dall'angelo, S., Harrison, W. T. A., Lichtman, A. H., Ross, R. A., Zanda, M., & Greig, I. R. (2019). The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB1 Receptor Positive Allosteric Modulators (PAMs). Journal of Medicinal Chemistry, 62(10), 5049-5062. https://doi.org/10.1021/acs.jmedchem.9b00252

Tseng, C-C, Baillie, G, Donvito, G, Mustafa, MA, Juola, SE, Zanato, C, Massarenti, C, Dall'angelo, S , Harrison, WTA, Lichtman, AH, Ross, RA, Zanda, M & Greig, IR 2019, 'The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB1 Receptor Positive Allosteric Modulators (PAMs)', Journal of Medicinal Chemistry, vol. 62, no. 10, pp. 5049-5062. https://doi.org/10.1021/acs.jmedchem.9b00252

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abstract = "The first generation of CB1 positive allosteric modulators (PAMs; e.g., ZCZ011) featured a 3-indolyl-nitromethane structure. Although a small number of drugs include the nitro group, it is generally not regarded as being “drug-like”, and this is particularly true for aliphatic nitro groups. There are very few case studies where an appropriate bioisostere replaced a nitro group that had a direct role in binding. This may be indicative of the difficulty of replicating its binding interactions. Herein we report the design and synthesis of ligands targeting the allosteric binding site on the CB1 cannabinoid receptor, in which a CF3 group successfully replaced the aliphatic NO2. In general, the CF3-bearing compounds were more potent than their NO2 equivalents and also showed improved in vitro metabolic stability. The CF3-analogue (1) with the best balance of properties was selected for further pharmacological evaluation. Pilot in vivo studies showed that (±)-1 has similar activity to (±)-ZCZ011, with both showing promising efficacy in a mouse model of neuropathic pain.",

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AU - Mustafa, Mohammed A.

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The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB1 Receptor Positive Allosteric Modulators (PAMs)

Abstract

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Iain Greig

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The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB1 Receptor Positive Allosteric Modulators (PAMs)

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