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)

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 languageEnglish
Pages (from-to)5049-5062
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number10
Early online date3 May 2019
DOIs
Publication statusPublished - 2019

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Cannabinoid Receptor CB1
Allosteric Site
Neuralgia
Pharmaceutical Preparations
Binding Sites
Pharmacology
Ligands
nitromethane
In Vitro Techniques

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine

Cite this

The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB1 Receptor Positive Allosteric Modulators (PAMs). / Tseng, Chih-Chung; Baillie, Gemma; Donvito, Giulia; Mustafa, Mohammed A.; Juola, Sophie E.; Zanato, Chiara; Massarenti, Chiara; Dall'angelo, Sergio; Harrison, William T. A.; Lichtman, Aron H.; Ross, Ruth A.; Zanda, Matteo (Corresponding Author); Greig, Iain R. (Corresponding Author).

In: Journal of Medicinal Chemistry, Vol. 62, No. 10, 2019, p. 5049-5062.

Research output: Contribution to journalArticle

Tseng, Chih-Chung ; Baillie, Gemma ; Donvito, Giulia ; Mustafa, Mohammed A. ; Juola, Sophie E. ; Zanato, Chiara ; Massarenti, Chiara ; Dall'angelo, Sergio ; Harrison, William T. A. ; Lichtman, Aron H. ; Ross, Ruth A. ; Zanda, Matteo ; Greig, Iain R. / The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB1 Receptor Positive Allosteric Modulators (PAMs). In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 10. pp. 5049-5062.
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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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