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Issue 8, 2017
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Bioisosteric replacement of central 1,2,4-oxadiazole ring of high affinity CB2 ligands by regioisomeric 1,3,4-oxadiazole ring

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Abstract

It has been reported that bioisosteric replacement of an 1,2,4-oxadiazole ring by an 1,3,4-oxadiazole ring leads to higher polarity, reduced metabolic degradation by human liver microsomes and reduced interaction with hERG channels. In a seven to eight step synthesis 1,3,4-oxadiazles 9a–c were synthesized as bioisosteric analogs of high-affinity but rather lipophilic CB2 ligands 1a–c containing an 1,2,4-oxadiazole ring. The 1,3,4-oxadiazole derivatives 9a and 9b show 10- and 50-fold reduced CB2 affinity compared to the 1,2,4-oxadiazole derivatives 1a and 1b, respectively. However, the 1,3,4-oxadiazole 9a has high CB2 affinity (Ki = 25 nM) and high selectivity over the CB1 receptor.

Graphical abstract: Bioisosteric replacement of central 1,2,4-oxadiazole ring of high affinity CB2 ligands by regioisomeric 1,3,4-oxadiazole ring

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Publication details

The article was received on 12 Jun 2017, accepted on 14 Jul 2017 and first published on 19 Jul 2017


Article type: Research Article
DOI: 10.1039/C7MD00296C
Citation: Med. Chem. Commun., 2017,8, 1697-1705
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    Bioisosteric replacement of central 1,2,4-oxadiazole ring of high affinity CB2 ligands by regioisomeric 1,3,4-oxadiazole ring

    D. Heimann, C. Lueg, H. de Vries, B. Frehland, D. Schepmann, L. H. Heitman and B. Wünsch, Med. Chem. Commun., 2017, 8, 1697
    DOI: 10.1039/C7MD00296C

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