Search

Abstract Various disorders are accompanied by histamine‐independent itching, which is often resistant to the currently available therapies. Here, it is reported that the pharmacological activation of Slack (Kcnt1, KNa1.1), a potassium channel highly expressed in itch‐sensitive sensory neurons, has therapeutic potential for the treatment of itching. Based on the Slack‐activating antipsychotic drug, loxapine, a series of new derivatives with improved pharmacodynamic and pharmacokinetic profiles is designed that enables to validate Slack as a pharmacological target in vivo. One of these new Slack activators, compound 6, exhibits negligible dopamine D2 and D3 receptor binding, unlike loxapine. Notably, compound 6 displays potent on‐target antipruritic activity in multiple mouse models of acute histamine‐independent and chronic itch without motor side effects. These properties make compound 6 a lead molecule for the development of new antipruritic therapies targeting Slack.

Abstract A novel oxadiazolone‐based method for the synthesis of 3‐aminobenzisoxazoles by N−O bond formation and of 2‐aminobenzoxazoles through a Tiemann‐type rearrangement has been developed. The synthesis of these two pharmaceutically relevant heterocycles was realized by an unexplored retrosynthetic disconnection using a cyclic nitrenoid precursor‐based strategy. The selective formation of the two isomers was significantly influenced by steric and electronic effects of substituents. However, tetrabutylammonium chloride (TBACl) efficiently promoted the Tiemann‐type rearrangement over N−O bond formation. Control experiments indicate that deprotonation of the phenol induces both rearrangements.