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


ABSTRACT: The first generation of CB1 positive allosteric modulators (e.g., ZCZ011) featured a 3-nitroalkyl-2-phenyl-indole 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.

SUBMITTER: Tseng CC 

PROVIDER: S-EPMC7871173 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB<sub>1</sub> Receptor Positive Allosteric Modulators.

Tseng Chih-Chung CC   Baillie Gemma G   Donvito Giulia G   Mustafa Mohammed A MA   Juola Sophie E SE   Zanato Chiara C   Massarenti Chiara C   Dall'Angelo Sergio S   Harrison William T A WTA   Lichtman Aron H AH   Ross Ruth A RA   Zanda Matteo M   Greig Iain R IR  

Journal of medicinal chemistry 20190514 10


The first generation of CB<sub>1</sub> positive allosteric modulators (e.g., ZCZ011) featured a 3-nitroalkyl-2-phenyl-indole 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 intera  ...[more]

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