Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
J Med Chem. 2017 Feb 9;60(3):1105-1125. doi: 10.1021/acs.jmedchem.6b01496. Epub 2016 Dec 21.
Current pain therapeutics suffer from undesirable psychotropic and sedative side effects, as well as abuse potential. Glycine receptors (GlyRs) are inhibitory ligand-gated ion channels expressed in nerves of the spinal dorsal horn, where their activation is believed to reduce transmission of painful stimuli. Herein, we describe the identification and hit-to-lead optimization of a novel class of tricyclic sulfonamides as allosteric GlyR potentiators. Initial optimization of high-throughput screening (HTS) hit 1 led to the identification of 3, which demonstrated ex vivo potentiation of glycine-activated current in mouse dorsal horn neurons from spinal cord slices. Further improvement of potency and pharmacokinetics produced in vivo proof-of-concept tool molecule 20 (AM-1488), which reversed tactile allodynia in a mouse spared-nerve injury (SNI) model. Additional structural optimization provided highly potent potentiator 32 (AM-3607), which was cocrystallized with human GlyRα3 to afford the first described potentiator-bound X-ray cocrystal structure within this class of ligand-gated ion channels (LGICs).
目前的疼痛治疗方法存在不良的精神和镇静副作用，以及滥用的可能性。甘氨酸受体（GlyRs）是在脊髓背角神经中表达的抑制性配体门控离子通道，其激活被认为可以减少疼痛刺激的传递。在此，我们描述了一种新型三环磺酰胺类化合物作为变构甘氨酸受体激动剂的鉴定和先导优化。高内涵筛选（HTS）命中物 1 的初步优化导致了 3 的鉴定，其在脊髓切片中的小鼠背角神经元中显示出甘氨酸激活电流的体外增强作用。进一步提高效力和药代动力学产生了体内概念验证工具分子 20（AM-1488），它在小鼠 spared-nerve injury（SNI）模型中逆转触觉过敏。额外的结构优化提供了高度有效的激动剂 32（AM-3607），其与人类 GlyRα3 共结晶，提供了该配体门控离子通道（LGICs）类中第一个描述的激动剂结合的 X 射线共晶结构。
