Novel therapeutic approach for NASH

NASH 的新治疗方法

基本信息

  • 批准号:
    10616609
  • 负责人:
  • 金额:
    $ 51.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-06-04 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

The overall goal of this project is to develop peripherally restricted partial agonists of the cannabinoid receptors (CB1 and CB2) for the treatment of non-alcoholic steatohepatitis (NASH). These compounds are expected to mimic the peripheral effects of THC ((−)-trans-Δ⁹-tetrahydrocannabinol), the only known orthosteric ligand of the CB receptors in marijuana while avoiding adverse CNS related side-effects. There are two known cannabinoid receptors – CB1 and CB2. The CB1 receptor is highly expressed on neurons of the CNS along with certain peripheral organs like the liver, pancreas, skeletal muscle and adipose tissue. The CB2 receptor is mostly expressed on immune cells Epidemiological studies indicate that marijuana users have reduced rates of NASH, type 2 diabetes and obesity. These contrarian effects are in sharp contrast to known orexigenic effects of marijuana via the CNS. These observations can be explained by disparate pharmacological effects of THC – a partial agonist. A partial agonist can act like a traditional agonist when excess receptors are present. However, a partial agonist can also act as a functional antagonist when number of receptors is limited by competing with a full agonist and by reducing downstream signaling. In the injured liver, the expression of CB1 is low to moderate but there is a large influx of CB2 expressing immune cells. Further, expression of the full agonist endocannabinoid 2-AG is ~1000-fold higher than that of the partial agonist AEA. We hypothesized that in NASH a partial agonist might be able to reduce fatty liver via functional antagonism of CB1 while producing anti- inflammatory effects by targeting CB2. We successfully tested this hypothesis using a well characterized partial agonist of CB receptors and an early lead compound in a model of NASH. Continuation of our preliminary studies is proposed through 3 integrated specific aims: (1) Synthesize partial CB receptor agonists that are peripherally restricted. We have started to explore a primary indazole scaffold and a secondary pyrazole scaffold to produce partial agonists of CB receptors that have limited CNS penetration. Continued refinement of early leads will lead to compounds with optimized drug-like properties. (2) Perform pharmacological characterization using various functional and binding assays and ADMET profiling of synthesized compounds to identify promising leads. Select compounds will undergo pharmacokinetic evaluation and behavioral profiling to rule out CNS-effects. (3) Perform efficacy testing in NASH models. We propose to evaluate our most promising leads in models of NASH for efficacy. In tandem, we will assess various biomarkers of efficacy and perform receptor occupancy studies to identify an optimized mature lead and two backups for further development.
该项目的总体目标是开发大麻素受体的外周限制性部分激动剂

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Discovery of 1,3-disubstituted pyrazole peripheral cannabinoid receptor partial agonists.
1,3-二取代吡唑外周大麻素受体部分激动剂的发现。
  • DOI:
    10.1016/j.bmcl.2023.129430
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    2.7
  • 作者:
    Amato,George;Runyon,Scott;Vasukuttan,Vineetha;Decker,AnnM;Gay,ElaineA;Laudermilk,Lucas;Maitra,Rangan
  • 通讯作者:
    Maitra,Rangan
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RANGAN MAITRA其他文献

RANGAN MAITRA的其他文献

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{{ truncateString('RANGAN MAITRA', 18)}}的其他基金

Conduct Confirmatory and Specialized In Vitro Testing and Screening of Interventional Agents in Standard Formats
以标准格式对介入药物进行验证性和专门的体外测试和筛选
  • 批准号:
    10925108
  • 财政年份:
    2023
  • 资助金额:
    $ 51.8万
  • 项目类别:
Conduct In Vitro Screening of Interventional Agents in High Throughput Screening (HTS) Formats: High Throughput Screening to Identify HIV Inhibitors
以高通量筛选 (HTS) 形式对介入药物进行体外筛选:通过高通量筛选识别 HIV 抑制剂
  • 批准号:
    10925107
  • 财政年份:
    2023
  • 资助金额:
    $ 51.8万
  • 项目类别:
Preclinical Services for HIV Therapeutics: QA/QC Plan and Task Order Initiation Meeting
HIV 治疗的临床前服务:QA/QC 计划和任务订单启动会议
  • 批准号:
    10397451
  • 财政年份:
    2021
  • 资助金额:
    $ 51.8万
  • 项目类别:
Novel therapeutic approach for NASH
NASH 的新治疗方法
  • 批准号:
    10426164
  • 财政年份:
    2020
  • 资助金额:
    $ 51.8万
  • 项目类别:
Novel therapeutic approach for NASH
NASH 的新治疗方法
  • 批准号:
    10179374
  • 财政年份:
    2020
  • 资助金额:
    $ 51.8万
  • 项目类别:
APJ receptor agonism for metabolic syndrome
APJ 受体激动剂治疗代谢综合征
  • 批准号:
    9899980
  • 财政年份:
    2017
  • 资助金额:
    $ 51.8万
  • 项目类别:
APJ receptor agonism for metabolic syndrome
APJ 受体激动剂治疗代谢综合征
  • 批准号:
    9239698
  • 财政年份:
    2017
  • 资助金额:
    $ 51.8万
  • 项目类别:
Investigation of Synthetic Cannabinoid Exposures and Pharmacological Consequences
合成大麻素暴露和药理学后果的调查
  • 批准号:
    10521643
  • 财政年份:
    2016
  • 资助金额:
    $ 51.8万
  • 项目类别:
Investigation of Synthetic Cannabinoid Exposures and Pharmacological Consequences
合成大麻素暴露和药理学后果的调查
  • 批准号:
    10704595
  • 财政年份:
    2016
  • 资助金额:
    $ 51.8万
  • 项目类别:
In vivo probes for the APJ receptor.
APJ 受体的体内探针。
  • 批准号:
    9095375
  • 财政年份:
    2014
  • 资助金额:
    $ 51.8万
  • 项目类别:

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