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The trifluoromethyl group as a bioisosteric replacement of the aliphatic nitro group in CB1 receptor positive allosteric modulators

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posted on 08.05.2019, 13:18 by Chih-Chung Tseng, Gemma Baillie, Giulia Donvito, Mohammed Mustafa, Sophie Juola, Chiara Zanato, Chiara Massarenti, Sergio Dall'Angelo, William T. Harrison, Aron H. Lichtman, Ruth Ross, Matteo Zanda, Iain R. Greig
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.

Funding

Signal Pharma and the Canadian Institutes of Health Research Proof of Principle grants PPP-125784 and PP2-139101, NIH grants R01DA039942, P30DA033934 and VCU School of Pharmacy start-up funds (A.H.L.).

History

School

  • Science

Department

  • Chemistry

Published in

Journal of Medicinal Chemistry

Volume

62

Issue

10

Pages

5049-5062

Citation

TSENG, C-C. ... et al, 2019. The trifluoromethyl group as a bioisosteric replacement of the aliphatic nitro group in CB1 receptor positive allosteric modulators. Journal of Medicinal Chemistry, 62 (10), pp.5049-5062.

Publisher

© American Chemical Society

Version

AM (Accepted Manuscript)

Publisher statement

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.

Acceptance date

03/05/2019

Publication date

2019-05-03

Copyright date

2019

ISSN

0022-2623

eISSN

1520-4804

Language

en

Usage metrics

Loughborough Publications

Keywords

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