Capstick Rory A, Bollinger Sean R, Engers Julie L, Long Madeline F, Chang Sichen, Luscombe Vincent B, Rodriguez Alice L, Niswender Colleen M, Bridges Thomas M, Boutaud Olivier, Conn P Jeffrey, Engers Darren W, 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 Jul 3;15(8):1358-1366. doi: 10.1021/acsmedchemlett.4c00249. eCollection 2024 Aug 8.
This Letter details our efforts to develop novel tricyclic muscarinic acetylcholine receptor subtype 4 (M) 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-]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-]pyrimidin-4-amine core and 8-chloro-7,9-dimethylpyrido[3',2':4,5]furo[3,2-]pyrimidin-4-amine core. Both tricyclic cores displayed low nanomolar potency against human M and greatly reduced cytochrome P450 inhibition when compared with parent compound .
本信函详细介绍了我们开发具有改善药理学特性的新型三环毒蕈碱型乙酰胆碱受体亚型4（M4）正变构调节剂（PAM）支架的工作。这一努力涉及一种“回连”策略，以取代3-氨基-5-氯-4,6-二甲基噻吩并[2,3-b]吡啶-2-甲酰胺核心，从而发现了两个新型三环核心：一个8-氯-9-甲基吡啶并[3',2':4,5]噻吩并[3,2-b]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-b]嘧啶-4-胺核心。与母体化合物相比，这两个三环核心对人M4均显示出低纳摩尔效力，并且细胞色素P450抑制作用大大降低。
