Engers Julie L, Bollinger Sean R, Gregro Alison R, Capstick Rory A, Spearing Paul K, Long Madeline F, Tarr James C, Watson Katherine J, Chang Sichen, Luscombe Vincent B, Rodriguez Alice L, Cho Hyekyung P, Qi Aidong, Niswender Colleen M, Bubser Michael, Gould Robert W, Robb William Hudson, Byun Nellie, Gore John, Jones Carrie K, Thomsen Morten S, 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 Chem Neurosci. 2025 Jun 4;16(11):2141-2162. doi: 10.1021/acschemneuro.5c00277. Epub 2025 May 26.
Herein, we report the structure-activity relationship to develop novel tricyclic M positive allosteric modulator scaffolds with improved pharmacological properties. This endeavor involved modifying a 5-amino-3,4-dimethylthieno[2,3-]pyridazine-6-carboxamide core via a "tie-back" strategy to discover a novel tricyclic 3,4-dimethylpyrimido[4',5':4,5]thieno[2,3-]pyridazine core. From this exercise, / was identified as a preclinical candidate, which displays low nanomolar potency against both human and rat M. Moreover, is highly brain penetrant, has an overall superior pharmacological and DMPK profile to previously reported M PAMs, and demonstrates efficacy in preclinical models of antipsychotic-like activity.
在此，我们报告了结构-活性关系，以开发具有改善药理特性的新型三环M型正变构调节剂支架。这项工作涉及通过“回拉”策略修饰5-氨基-3,4-二甲基噻吩并[2,3-]哒嗪-6-甲酰胺核心，以发现新型三环3,4-二甲基嘧啶并[4',5':4,5]噻吩并[2,3-]哒嗪核心。通过这项工作，/被确定为临床前候选药物，它对人和大鼠M均表现出低纳摩尔效力。此外，/具有高度的脑渗透性，与先前报道的M型PAMs相比，具有总体上更优越的药理和药物代谢动力学特征，并在抗精神病样活性的临床前模型中显示出疗效。
