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IF 4.1 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

ACS Chemical Neuroscience Pub Date : 2025-02-19 Epub Date: 2025-02-05 DOI:10.1021/acschemneuro.5c00014

Carson W Reed, Jacob F Kalbfleisch, Jeremy A Turkett, Trevor A Trombley, Paul K Spearing, Daniel H Haymer, Marc Quitalig, Jonathan W Dickerson, Daniel J Foster, Annie L Blobaum, Olivier Boutaud, Hyekyung P Cho, Colleen M Niswender, Jerri M Rook, Henning Priepke, Heiko Sommer, Stefan Scheuerer, Daniel Ursu, P Jeffrey Conn, Bruce J Melancon, Craig W Lindsley

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引用次数: 0

摘要

在此，我们报告了对代谢谷氨酸受体亚型 1（mGlu1）正异位调节剂（PAM）VU6024578/BI02982816 的进一步化学优化以及 VU6033685/BI1752 的发现。PAM VU6033685/BI1752 是通过一个迭代过程开发的，在呋喃基（一种潜在的毒性分子）被 N-连接的吡唑取代后，多样性筛选确定了一个喹啉核心，并进一步截断为吡啶支架。事实证明，PAM VU6033685/BI1752 是一种强效且具有选择性的 mGlu1 PAM，在苯丙胺诱导的过度运动（AHL）和新物体识别（NOR）中均有疗效，且具有明确的药代动力学-药效动力学（PK/PD）关系。VU6024578/BI02982816对大鼠有效且耐受性良好，但对狗无效，而VU6033685/BI1752对大鼠和狗均有不良反应（AEs）。在两种不同的 mGlu1 PAM 化学型中出现的这些不良反应给这一本来很有希望解决精神分裂症患者多种症状群的分子靶点蒙上了阴影。

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Further Optimization of the mGlu₁ PAM VU6024578/BI02982816: Discovery and Characterization of VU6033685.

Herein, we report the further chemical optimization of the metabotropic glutamate receptor subtype 1 (mGlu₁) positive allosteric modulator (PAM) VU6024578/BI02982816 and the discovery of VU6033685/BI1752. PAM VU6033685/BI1752 was developed through an iterative process wherein, after the furanyl moiety (a potential toxicophore) was replaced by an N-linked pyrazole, a diversity screen identified a quinoline core, which was further truncated to a pyridine scaffold. PAM VU6033685/BI1752 proved to be a potent and selective mGlu₁ PAM with efficacy in both amphetamine-induced hyperlocomotion (AHL) and novel object recognition (NOR) with a clear pharmacokinetic-pharmacodynamic (PK/PD) relationship. VU6024578/BI02982816 was efficacious and well tolerated in rats but not dogs, whereas VU6033685/BI1752 elicited adverse events (AEs) in both rats and dogs. These AEs, noted in two distinct mGlu₁ PAM chemotypes, cast a shadow on an otherwise promising molecular target to address multiple symptom clusters in schizophrenic patients.

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来源期刊

ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL

CiteScore

9.20

自引率

4.00%

发文量

323

审稿时长

1 months

期刊介绍： ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research