Bioisosteric replacement of central 1,2,4-oxadiazole ring of high affinity CB2 ligands by regioisomeric 1,3,4-oxadiazole ring,RSC Medicinal Chemistry

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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
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-07-19 00:00:00 , DOI: 10.1039/c7md00296c
Dominik Heimann _{1,

2,

3} , Corinna Lueg _{1,

2,

3} , Henk de Vries _{4,

5,

6,

7,

8} , Bastian Frehland _{1,

2,

3} , Dirk Schepmann _{1,

2,

3} , Laura H. Heitman _{4,

5,

6,

7,

8} , Bernhard Wünsch _{1,

2,

3,

9,

10}

Affiliation

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 (K_i = 25 nM) and high selectivity over the CB₁ receptor.

中文翻译：

高亲和力CB ₂配体的中心1,2,4-恶二唑环被区域异构的1,3,4-恶二唑环取代

据报道，用1,3,4-恶二唑环生物等位取代1,2,4-恶二唑环可导致更高的极性，减少的人肝微粒体代谢降解以及减少与hERG通道的相互作用。在七到八步的合成过程中，合成了1,3,4-恶二唑9a-c作为具有高亲和力但亲脂性CB ₂配体1a-c的生物立体异构体，其中CB ₂配体1a-c含有1,2,4-恶二唑环。1,3,4-恶二唑衍生物9a和9b分别比1,2,4-恶二唑衍生物1a和1b降低了10倍和50倍的CB ₂亲和力。但是1,3,4-恶二唑9a具有较高的CB ₂亲和力（K _i = 25 nM）和对CB ₁受体的高选择性。

更新日期：2017-08-16

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