Discovery of VU6016235: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M₄ Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM).

IF 3.9 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

ACS Chemical Neuroscience Pub Date : 2024-09-24 DOI:10.1021/acschemneuro.4c00465

Julie L Engers, Logan A Baker, Sichen Chang, Vincent B Luscombe, Alice L Rodriguez, Colleen M Niswender, Hyekyung P Cho, Michael Bubser, Analisa Thompson Gray, Carrie K Jones, Weimin Peng, Jerri M Rook, Thomas M Bridges, Olivier Boutaud, P Jeffrey Conn, Darren W Engers, Craig W Lindsley, Kayla J Temple

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Abstract

Herein, we report structure-activity relationship (SAR) studies to develop novel tricyclic M₄ PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace a 5-amino-2,4-dimethylthieno[2,3-d]pyrimidine-6-carboxamide core, which led to the discovery of two novel tricyclic cores. While both tricyclic cores displayed low nanomolar potency against both human and rat M₄ and were highly brain-penetrant, the 2,4-dimethylpyrido[4',3':4,5]thieno[2,3-d]pyrimidine tricycle core provided lead compound, VU6016235, with an overall superior pharmacological and drug metabolism and pharmacokinetics (DMPK) profile, as well as efficacy in a preclinical antipsychotic animal model.

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发现 VU6016235：一种高选择性、口服生物可用性和结构独特的三环 M4 肌卡因乙酰胆碱受体正性异位调节剂 (PAM)。

在本文中，我们报告了结构-活性关系 (SAR) 研究，以开发药理特性更好的新型三环 M4 PAM 支架。这项研究采用 "回接 "策略取代了 5-氨基-2,4-二甲基噻吩并[2,3-d]嘧啶-6-甲酰胺核心，从而发现了两种新型三环核心。虽然这两种三环核心对人类和大鼠的 M4 都显示出低纳摩尔的药效，并且具有很强的脑穿透性，但 2,4-二甲基吡啶并[4',3':4,5]噻吩并[2,3-d]嘧啶三环核心为先导化合物 VU6016235 提供了全面优异的药理、药物代谢和药代动力学（DMPK）特征，以及在临床前抗精神病动物模型中的疗效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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