Discovery and development of novel glycine transporter-2 inhibitors for the treatment of neuropathic pain

发现和开发用于治疗神经性疼痛的新型甘氨酸转运蛋白 2 抑制剂

基本信息

  • 批准号:
    10592522
  • 负责人:
  • 金额:
    $ 45.52万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

It is estimated that 7–10% of the general population suffers from chronic neuropathic pain and associated annual economic costs exceed $160 billion in the US. Current analgesics used to treat chronic neuropathic pain lack efficacy, induce dose-limiting side effects or present a significant risk of tolerance and abuse. Thus, the discovery of novel analgesics that provide meaningful pain relief with improved safety, tolerability and reduced abuse potential remains an unmet medical need. Among the various mechanisms involved in pathological pain, disinhibition of nociceptive signaling from the spinal cord to the higher CNS plays a critical role. Indeed, we and others have shown that inhibitory glycinergic neurotransmission in the dorsal horn is impaired in pathological pain states. Thus, it has been proposed that enhancing spinal glycinergic neurotransmission could reduce nociceptor signaling and provide analgesia. Glycine transporter-2 (GlyT-2) regulates extracellular glycine concentrations in the CNS and presents a highly attractive target to augment impaired spinal inhibitory signaling. Indeed, GlyT-2 inhibitors have demonstrated efficacy in several rodent models of acute and chronic pain. Recent studies suggest that either partial or reversible GlyT-2 inhibition can potentially circumvent potential mechanism-based adverse effects and provide analgesics with a suitable balance of efficacy and tolerability. We synthesized 60 bioactive lipid allosteric partial inhibitors exhibiting varying degrees of potency and %maximal inhibition and our most potent compound of this class enhances tonic glycinergic currents ex vivo in rat spinal cord slices without depleting presynaptic glycine reloading and produces in vivo dose-dependent efficacy in PNL rats without adverse effects. Separately, we synthesized 18 novel GlyT-2 inhibitor hit compounds derived from ORG-25543 that exhibit reproducible variations in reversibility and transport recovery using a washout assay protocol. From these two libraries, we propose conducting a dual-pronged medicinal chemistry campaign to identify optimized compounds possessing favorable potency, binding profiles and ADME characteristics suitable for measuring effects in spinal cord slices and in vivo PK. Selected compounds will be screened in the rat PNL model to assess analgesic efficacy and in behavioral models for dose-limiting effects and TI. Our proposal seeks support to optimize our hit compounds to provide selective and orally bioavailable GlyT-2 inhibitors for further development and eventual human clinical trials in neuropathic pain. The studies outlined in this proposal seek to conduct medicinal chemistry optimization using a battery of primary, secondary, counter-screen, and ADMET assays to assess potency, binding profile (%maximal inhibition, reversibility and mechanism of binding), selectivity and drug- like properties (Specific Aim 1), and assess PK, preclinical analgesic efficacy and tolerability of advanced compounds in animal models of neuropathic pain and motor behavior at different stages of compound optimization (Specific Aim 2).
据估计,总人口中有7-10%的人患有慢性神经性疼痛及相关疾病

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Glycine Transporter 2: Mechanism and Allosteric Modulation.
  • DOI:
    10.3389/fmolb.2021.734427
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    5
  • 作者:
    Frangos ZJ;Cantwell Chater RP;Vandenberg RJ
  • 通讯作者:
    Vandenberg RJ
Opioid overdose and tolerance: is the recruitment of β-arrestin to the µ-receptor involved?
阿片类药物过量和耐受性:是否涉及β-抑制蛋白向μ-受体的募集?
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Christopher L. Cioffi其他文献

Novel serotonin type 3 receptor partial agonists for the potential treatment of irritable bowel syndrome
  • DOI:
    10.1016/j.bmcl.2010.11.080
  • 发表时间:
    2011-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    David D. Manning;Christopher L. Cioffi;Alexander Usyatinsky;Kevin Fitzpatrick;Liaqat Masih;Cheng Guo;Zhenjun Zhang;Sok Hui Choo;M. Inthikhab Sikkander;Kristen N. Ryan;Jennifer Naginskaya;Carla Hassler;Svetlana Dobritsa;Jonathan D. Wierschke;William G. Earley;Amy S. Butler;Catherine A. Brady;Nicholas M. Barnes;Marlene L. Cohen;Peter R. Guzzo
  • 通讯作者:
    Peter R. Guzzo
Identification and characterisation of lipids that are positive allosteric modulators of glycine receptors
  • DOI:
    10.1016/j.bpj.2022.11.2138
  • 发表时间:
    2023-02-10
  • 期刊:
  • 影响因子:
  • 作者:
    Casey I. Gallagher;Yie Chang Lin;Arvind Kumar;Damian Ha;Christopher L. Cioffi;Sudha Chakrapani;Megan L. O'Mara;Robert J. Vandenberg
  • 通讯作者:
    Robert J. Vandenberg
Design, synthesis, and SAR of <em>N</em>-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1
  • DOI:
    10.1016/j.bmcl.2013.01.006
  • 发表时间:
    2013-03-01
  • 期刊:
  • 影响因子:
  • 作者:
    Christopher L. Cioffi;Mark A. Wolf;Peter R. Guzzo;Kashinath Sadalapure;Visweswaran Parthasarathy;Dattatraya Dethe;Jun-Ho Maeng;Edmund Carulli;David T.J. Loong;Xiao Fang;Min Hu;Priya Gupta;Mark Chung;Mei Bai;Nick Moore;Michele Luche;Yuri Khmelnitsky;Patrick L. Love;Megan A. Watson;Andrew J. Mhyre
  • 通讯作者:
    Andrew J. Mhyre

Christopher L. Cioffi的其他文献

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{{ truncateString('Christopher L. Cioffi', 18)}}的其他基金

Polypharmacological approach to treatment of Stargardt disease
治疗 Stargardt 病的多药理学方法
  • 批准号:
    10561110
  • 财政年份:
    2023
  • 资助金额:
    $ 45.52万
  • 项目类别:
Discovery and development of novel glycine transporter-2 inhibitors for the treatment of neuropathic pain
发现和开发用于治疗神经性疼痛的新型甘氨酸转运蛋白 2 抑制剂
  • 批准号:
    10201549
  • 财政年份:
    2019
  • 资助金额:
    $ 45.52万
  • 项目类别:
Discovery and development of novel glycine transporter-2 inhibitors for the treatment of neuropathic pain
发现和开发用于治疗神经性疼痛的新型甘氨酸转运蛋白 2 抑制剂
  • 批准号:
    10025586
  • 财政年份:
    2019
  • 资助金额:
    $ 45.52万
  • 项目类别:

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