Childress Elizabeth S, Capstick Rory A, Crocker Katherine E, Ledyard Miranda L, Bender Aaron M, Maurer Mallory A, Billard Natasha B, Cho Hyekyung P, Rodriguez Alice L, Niswender Colleen M, Peng Weimin, Rook Jerri M, Chang Sichen, Blobaum Anna L, Boutaud Olivier, Thompson Gray Analisa, Jones Carrie K, Conn P Jeffrey, Felts Andrew S, Lindsley Craig W, Temple Kayla J
Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
ACS Med Chem Lett. 2024 Nov 18;15(12):2210-2219. doi: 10.1021/acsmedchemlett.4c00481. eCollection 2024 Dec 12.
This Letter details our efforts to develop novel, non-acetylene-containing metabotropic glutamate receptor subtype 5 (mGlu) 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 , a highly brain penetrant and selective mGlu NAM which displayed moderate potency against both human and rat mGlu. Moreover, has overall improved pharmacological and drug metabolism and pharmacokinetic profiles when compared to its predecessor compounds. Most notably, exhibits low predicted human hepatic clearance, a clean cytochrome P450 profile, and minimal inhibition of the dopamine transporter.
本信函详述了我们开发新型、不含乙炔的代谢型谷氨酸受体5（mGlu）负变构调节剂（NAMs）的努力，这些调节剂具有改善的药理学特性。这项工作涉及用各种五元杂环取代作为代谢易损性的醚键连接嘧啶部分。通过这项工作，我们鉴定出了一种具有高脑渗透性和选择性的mGlu NAM，它对人和大鼠的mGlu均表现出中等效力。此外，与之前的化合物相比，该化合物的药理学、药物代谢和药代动力学特性总体上有所改善。最值得注意的是，该化合物预测的人体肝脏清除率较低，细胞色素P450谱干净，对多巴胺转运体的抑制作用最小。
