Non-addictive Angiotensin AT2 inhibitors for neuropathic pain relief
用于缓解神经性疼痛的非成瘾性血管紧张素 AT2 抑制剂
基本信息
- 批准号:10645104
- 负责人:
- 金额:$ 60.74万
- 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:2020-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AGTR2 geneAbsence of pain sensationAffectAfferent NeuronsAffinityAmericanAnalgesicsAngiotensin ReceptorAngiotensinsAnimalsAnxietyBack PainBindingBiological AssayBrainBypassCanis familiarisCellsClinicalCoculture TechniquesCollaborationsComplexContractorDevelopmentDiabetes MellitusDoseDrug AddictionDrug KineticsDrug usageEconomic BurdenEpidemicEsthesiaGeneticGoalsGrantHepatotoxicityHerpes zoster diseaseHypersensitivityIn VitroInjectionsKnockout MiceLeadLigandsMacrophageMeasuresMediatingMedicalMedicineMembraneMental DepressionModelingMotivationMusNerve FibersNeuralgiaNeuritesNeuroimmuneNeuroimmunomodulationNeuronsNociceptorsOpiate AddictionOpioidOpioid AnalgesicsOralOutputPainPain managementPatientsPenetrationPeripheralPeripheral NervesPeripheral Nervous SystemPersonsPharmaceutical PreparationsPhasePhase II Clinical TrialsPostherpetic neuralgiaPostoperative PainPre-Clinical ModelPreparationProductionPropertyReceptor InhibitionReceptor SignalingRegulationResolutionRiskRodentRoleSafetySignal TransductionSocietiesStructural BiologistStructureStructure-Activity RelationshipSynthesis ChemistrySystemTestingTherapeuticToxicologyType 2 Angiotensin II Receptoraddictionanalogantagonistbehavior testbehavioral responsecardiovascular effectscellular targetingchemical synthesischemotherapychronic neuropathic painchronic painchronic pain reliefclinical candidateclinical developmentdrug discoverydrug seeking behaviorexperienceimprovedin vitro Assayin vitro Modelin vitro testingin vivoinhibitorlead optimizationlead seriesmouse modelmultidisciplinarynon-opioid analgesicnovelnovel strategiesopioid abuseopioid epidemicopioid overdosepain reliefpainful neuropathypre-clinicalpreclinical developmentprescription opioidreceptorresponsescaffoldscale upscreeningside effecttherapeutic target
项目摘要
Project Summary
Neuropathic chronic pain affects ~20 million of Americans and bears more than US$500 Billion burden on the
US economy. Moreover, the widespread use of addictive opioid painkillers for chronic pain is the major root of
the opioid abuse epidemics threatening the whole society. As only one in four patients with neuropathic pain
experiences pain relief with the current treatment options, discovery of new approaches to treating neuropathic
pain is an unmet medical need with a major impact on society. Targeting pain in peripheral neurons is a key
paradigm for effective and safe analgesia, which can naturally bypass the CNS-mediated side effects and
addiction. One of the most promising and advanced peripheral targets, angiotensin AT2 receptor is involved in
regulations of neuronal membrane excitability and neurite outgrowth of peripheral sensory neurons. Inhibition of
AT2R in PNS has shown effect in preclinical models of neuropathic pain, as well as in phase II clinical trials,
where the EMA401 drug demonstrated analgesia in patients with post-herpetic neuralgia. However, EMA401,
which had modest potency and suboptimal drug-like properties, has been terminated in May 2019 due to off-
target hepatotoxicity at high therapeutic doses. Lack of suitable AT2R candidates in pipeline calls for discovery
and development of new highly potent and safe AT2R antagonists for neuropathic pain. We have established a
structure-based drug discovery platform and used it to identify new lead chemotypes for AT2R antagonists. Our
current lead has affinity (Ki =56 nM) on par with the previous clinical candidate, but much higher ligand efficiency,
better drug-like properties and initial SAR suggesting high optimization potential. Moreover, recent
breakthroughs in understanding the neuroimmune functional role of AT2R in neuropathic pain helped us to
establish a set of cell-based functional assays, lack of which hampered previous development efforts. Using
these platforms, we plan to establish comprehensive SAR for our main and backup lead series, and develop a
screening funnel in the 1-year UG3 phase of the project. In close collaboration with the BPN steering committee,
consultants and contractors, this screening funnel will then be employed in UH3 phase to optimize the lead
potency, selectivity, ADMET and PK properties relevant for AT2R lead development, including peripheral
restriction that precludes CNS side effects. This would allow selection of clinical development candidate for pre-
development, IND-enabling studies and preparation of IND targeting post-herpetic neuralgia.
项目总结
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)
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Vadim Cherezov其他文献
Vadim Cherezov的其他文献
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{{ truncateString('Vadim Cherezov', 18)}}的其他基金
Non-addictive Angiotensin AT2 inhibitors for neuropathic pain relief
用于缓解神经性疼痛的非成瘾性血管紧张素 AT2 抑制剂
- 批准号:
10396694 - 财政年份:2020
- 资助金额:
$ 60.74万 - 项目类别:
Non-addictive Angiotensin AT2 inhibitors for neuropathic pain relief
用于缓解神经性疼痛的非成瘾性血管紧张素 AT2 抑制剂
- 批准号:
10405661 - 财政年份:2020
- 资助金额:
$ 60.74万 - 项目类别:
Structural biology of G protein-coupled receptors
G蛋白偶联受体的结构生物学
- 批准号:
9925243 - 财政年份:2018
- 资助金额:
$ 60.74万 - 项目类别:
Structural biology of G protein-coupled receptors
G蛋白偶联受体的结构生物学
- 批准号:
10396469 - 财政年份:2018
- 资助金额:
$ 60.74万 - 项目类别:
Structure guided design of photoselectable channelrhodopsins
光选择性通道视紫红质的结构引导设计
- 批准号:
9244699 - 财政年份:2016
- 资助金额:
$ 60.74万 - 项目类别:
Structure guided design of photoselectable channelrhodopsins
光选择性通道视紫红质的结构引导设计
- 批准号:
9360611 - 财政年份:2016
- 资助金额:
$ 60.74万 - 项目类别:
HT structure determination of GPCRs by LCP serial femtosecond nanocrystallography
LCP 系列飞秒纳米晶体学测定 GPCR 的 HT 结构
- 批准号:
9078982 - 财政年份:2014
- 资助金额:
$ 60.74万 - 项目类别:
HT structure determination of GPCRs by LCP serial femtosecond nanocrystallography
LCP 系列飞秒纳米晶体学测定 GPCR 的 HT 结构
- 批准号:
8612932 - 财政年份:2014
- 资助金额:
$ 60.74万 - 项目类别: