Discovery of VU6008677: A Structurally Distinct Tricyclic M4 Positive Allosteric Modulator with Improved CYP450 Profile

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-07-03 DOI:10.1021/acsmedchemlett.4c00249

Rory A. Capstick, Sean R. Bollinger, Julie L. Engers, Madeline F. Long, Sichen Chang, Vincent B. Luscombe, Alice L. Rodriguez, Colleen M. Niswender, Thomas M. Bridges, Olivier Boutaud, P. Jeffrey Conn, Darren W. Engers, Craig W. Lindsley, Kayla J. Temple

引用次数: 0

Abstract

This Letter details our efforts to develop novel tricyclic muscarinic acetylcholine receptor subtype 4 (M₄) positive allosteric modulator (PAM) scaffolds with improved pharmacological properties. This endeavor involved a “tie-back” strategy to replace the 3-amino-5-chloro-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core, which led to the discovery of two novel tricyclic cores: an 8-chloro-9-methylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine core and 8-chloro-7,9-dimethylpyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine core. Both tricyclic cores displayed low nanomolar potency against human M₄ and greatly reduced cytochrome P450 inhibition when compared with parent compound ML253.

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发现 VU6008677：一种结构独特的三环 M4 阳性异构调节剂，具有更好的 CYP450 特征

这封信详细介绍了我们为开发具有更好药理特性的新型三环类毒蕈碱乙酰胆碱受体亚型 4 (M4) 阳性异位调节剂 (PAM) 支架所做的努力。这项工作包括采用 "回接 "策略取代 3-氨基-5-氯-4,6-二甲基噻吩并[2,3-b]吡啶-2-甲酰胺核心，从而发现了两种新型三环核心：8-氯-9-甲基吡啶并[3′,2′:4,5]噻吩并[3,2-d]嘧啶-4-胺核心和 8-氯-7,9-二甲基吡啶并[3′,2′:4,5]呋喃并[3,2-d]嘧啶-4-胺核心。与母体化合物 ML253 相比，这两种三环核心化合物对人类 M4 的药效均为低纳摩尔，并大大降低了对细胞色素 P450 的抑制作用。

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 Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.