ABSTRACT

Introduction

The diverse neuro- and immunomodulatory effects of kynurenine pathway (KP) enzymes and metabolites exert offer possibilities for intervention in diseases such as autoimmunity, neurodegeneration, and neoplastic processes.

Areas covered

This review focuses on data obtained from the preclinical and clinical use of a KP metabolite analog and structurally related compounds. 4-Cl-KYN has completed clinical trials in depression without success. However, the good safety data give hope for further trials in suicide prevention, neuropathic pain, and dyskinesia. Quinoline-3-carboxamide derivatives laquinimod, paquinimod, and tasquinimod show structural similarities to kynurenines. Laquinimod and paquinimod show promising results in the treatment of autoimmune diseases, tasquinimod is considered primarily as an anti-cancer drug. Data available until 31 May 2020 at Clinicaltrials.gov and PubMed have been reviewed.

Expert opinion

The failure of 4-Cl-KYN for use as an anti-depressant may be related to inadequate concentration, or that the ketamine-like rapid anti-depressant effect is not produced via NMDAR modulation. Further clarification may emerge from studies involving higher drug concentration, and/or from identification of ketamine targets. Clinical application trials in very diverse indications of structurally related quinoline-3-carboxamides and the wide range of their mode of action warrant further studies permitting direct comparison of effects and better target identification.

中文翻译：

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犬尿氨酸和喹啉-3-甲酰胺类药物的开发进展。

摘要

介绍

犬尿氨酸途径 (KP) 酶和代谢物的多种神经和免疫调节作用为干预自身免疫、神经变性和肿瘤过程等疾病提供了可能性。

涵盖的领域

本综述侧重于从 KP 代谢物类似物和结构相关化合物的临床前和临床使用中获得的数据。4-Cl-KYN 已经完成了抑郁症的临床试验，但没有成功。然而，良好的安全性数据为进一步的自杀预防、神经性疼痛和运动障碍试验带来了希望。喹啉-3-羧酰胺衍生物拉喹莫德、paquinimod 和 tasquinimod 显示出与犬尿氨酸的结构相似性。Laquinimod 和 paquinimod 在治疗自身免疫性疾病方面显示出可喜的结果，tasquinimod 主要被认为是一种抗癌药物。Clinicaltrials.gov 和 PubMed 上截至 2020 年 5 月 31 日的数据已经过审查。

专家意见

4-Cl-KYN 不能用作抗抑郁药可能与浓度不足有关，或者氯胺酮样快速抗抑郁作用不是通过NMDAR 调制产生的。涉及更高药物浓度的研究和/或氯胺酮靶点的鉴定可能会产生进一步的澄清。在结构相关的喹啉-3-甲酰胺的各种适应症及其广泛的作用模式中进行的临床应用试验需要进一步研究，以便直接比较效果和更好的靶点识别。