Discovery of 4-(5-Membered)Heteroarylether-6-methylpicolinamide 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 : 2024-11-18 eCollection Date: 2024-12-12 DOI:10.1021/acsmedchemlett.4c00481

Elizabeth S Childress, Rory A Capstick, Katherine E Crocker, Miranda L Ledyard, Aaron M Bender, Mallory A Maurer, Natasha B Billard, Hyekyung P Cho, Alice L Rodriguez, Colleen M Niswender, Weimin Peng, Jerri M Rook, Sichen Chang, Anna L Blobaum, Olivier Boutaud, Analisa Thompson Gray, Carrie K Jones, P Jeffrey Conn, Andrew S Felts, Craig W Lindsley, Kayla J Temple

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Abstract

This Letter details our efforts to develop novel, non-acetylene-containing metabotropic glutamate receptor subtype 5 (mGlu₅) negative allosteric modulators (NAMs) with improved pharmacological properties. This endeavor involved replacing the ether-linked pyrimidine moiety, a metabolic liability, with various 5-membered heterocycles. From this exercise, we identified VU6043653, a highly brain penetrant and selective mGlu₅ NAM which displayed moderate potency against both human and rat mGlu₅. Moreover, VU6043653 has overall improved pharmacological and drug metabolism and pharmacokinetic profiles when compared to its predecessor compounds. Most notably, VU6043653 exhibits low predicted human hepatic clearance, a clean cytochrome P450 profile, and minimal inhibition of the dopamine transporter.

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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.