Bioisosteric replacement of central 1, 2, 4-oxadiazole ring of high affinity CB2 ligands by regioisomeric 1, 3, 4-oxadiazole ring. Issue 8 (25th July 2017)

• Record Type: Journal Article
• Authors: Heimann, Dominik; Lueg, Corinna; de Vries, Henk; Frehland, Bastian; Schepmann, Dirk; Heitman, Laura H.; Wünsch, Bernhard
• Is Part Of: MedChemComm. Volume 8:Issue 8(2017)
• Page Start: 1697
• Page End: 1705
• Publication Date: 2017-07-25
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19
• DOI: 10.1039/c7md00296c
• Languages: English
• ISSNs: 2040-2503

Abstract

Abstract : Three pairs of regioisomeric 1, 2, 4- and 1, 3, 4-oxadiazoles were synthesized as selective CB2 ligands. Although the 1, 3, 4-oxadiazoles should have better physicochemical and pharmacokinetic properties, their CB2 affinity was reduced. 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-oxadiazles9a–c were synthesized as bioisosteric analogs of high-affinity but rather lipophilic CB2 ligands1a–c containing an 1, 2, 4-oxadiazole ring. The 1, 3, 4-oxadiazole derivatives9a and9b show 10- and 50-fold reduced CB2 affinity compared to the 1, 2, 4-oxadiazole derivatives1a and1b, respectively. However, the 1, 3, 4-oxadiazole9a has high CB2 affinity ( K i = 25 nM) and high selectivity over the CB1 receptor.