Discovery of Thieno[3,2-b]pyridine-5-carboxamide and 2,3-Difluorobenzamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-04-22 eCollection Date: 2025-05-08 DOI:10.1021/acsmedchemlett.5c00119

Katherine E Crocker, Scott H Henderson, Rory A Capstick, David L Whomble, Aaron M Bender, Andrew S Felts, Changho Han, Julie L Engers, Natasha B Billard, Mallory A Maurer, Hyekyung P Cho, Alice L Rodriguez, Colleen M Niswender, Jordan O'Neill, Katherine J Watson, Sichen Chang, Anna L Blobaum, Olivier Boutaud, Weimin Peng, Jerri M Rook, P Jeffrey Conn, Craig W Lindsley, Kayla J Temple

引用次数: 0

Abstract

This Letter describes the discovery of novel mGlu₅ NAMs VU6031545 and VU6024945. Starting from previously reported picolinamide compounds, a structure-activity relationship study of various core isosteres was conducted, leading to the identification of thieno[3,2-b]pyridine-5-carboxamide and 2,3-difluorobenzamide as competent core replacements. These compounds are highly potent as well as brain penetrant with an IVIVC agreement and improved oral bioavailability in rats.

查看原文本刊更多论文

代谢性谷氨酸受体亚型5的Thieno[3,2-b]吡啶-5-羧酰胺和2,3-二氟苯酰胺负变构调节剂的发现

这封信描述了新的mGlu5 NAMs VU6031545和VU6024945的发现。从先前报道的picolinamide化合物开始，对各种核心同分异构体进行了构效关系研究，最终确定了噻吩[3,2-b]吡啶-5-羧基酰胺和2,3-二氟苯甲酰胺作为核心替代品。这些化合物是高效的，并且具有脑渗透性，具有IVIVC协议和改善大鼠的口服生物利用度。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

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.