Optimization of Antischistosomal Chemotypes
抗血吸虫化学型的优化
基本信息
- 批准号:10374891
- 负责人:
- 金额:$ 62.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-02-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdolescentAdultAffectAreaBinding ProteinsBiological AssayBloodCountryDatabasesDoseDrug KineticsDrug resistanceFeedbackGoalsHumanHydantoinsIn VitroIndividualIndolesInfectionInvestigationKnowledgeLactamsLeadMediatingMetabolicMicrosomesMissionMusOralOutcomeParasitesParasitic DiseasesPathway AnalysisPermeabilityPharmaceutical PreparationsPlasma ProteinsPraziquantelPropertyProtein IsoformsProteinsPublic HealthRattusResearchResistance developmentResortRing CompoundRoleSchistosomaSchistosoma japonicumSchistosoma mansoniSchistosomiasisSeriesSolubilityStructure-Activity RelationshipSulfonamidesTitrationsTreatment FailureTrematodaUnited States National Institutes of HealthWorkadaptive immune responsebasechemotherapycytotoxicitydesigndrug actiondrug candidatedrug developmentexperimental studygenotoxicityin silicoin vitro activityin vivoindexinginfection riskinnovationnovelnovel therapeuticsprogramsprospectivetranscriptomics
项目摘要
Schistosomiasis is a tropical parasitic disease caused by infections with flukes of the genus Schistosoma,
affecting as many as 200 million individuals worldwide, with 779 million living at risk of infection. A new drug for
schistosomiasis is urgently needed as praziquantel is currently the drug of last resort and the development of
resistance cannot be ignored, particularly in view of its large-scale use in many endemic. Our long-term goal is
to discover a new orally active single-dose antischistosomal drug with activities against all parasite stages and
with a novel mechanism of action. The objective of this proposal is to identify one or more antischistosomal
drug development candidates. To accomplish this objective, we will optimize four promising antischistosomal
chemotypes. We will also continue our investigation into the host-mediated antischistosomal mode of action of
aryl hydantoin drug candidate AR102. We propose four specific aims: 1) to synthesize and characterize target
compounds; 2) to assess pharmacokinetic properties and antischistosomal activity of target compounds; 3) to
further profile selected target compounds using more rigorous assays; and 4) to investigate the mode of action
of drug candidate AR102. Compound design will be informed by existing SAR and will maximize structural
diversity guided by prospective in silico physicochemical profiling. Based on iterative feedback from
physicochemical profiling, in vitro ADME, and cytotoxicity (SA 1), ex vivo and in vivo antischistosomal activity
and in vivo ADME (SA 2 and 3), new structural hypotheses will arise, and we will synthesize additional target
compounds. Target compounds will progress through the various assays using clearly defined progression
criteria. We suggest that this proposed research is innovative for several reasons First, the aryl hydantoins and
ozonides have proven in vivo antischistosomal efficacy, but have very low ex vivo (in vitro) activity, the reverse
of the usual situation where lead compounds have in vitro but no in vivo activity. Second, the azonine keto
lactam chemotype and backup tricyclic imidazolidin-4-one compound series are examples of relatively rare
medium-ring compounds (8 to 11 atoms). Third, we seek to demarcate the unique host-mediated mode of
action of antischistosomal drug candidate AR102. The expected outcome from this work is to identify one or
more antischistosomal drug development candidates effective against all parasite stages. For antischistosomal
drug candidate AR102, we will define its host-mediated antischistosomal mode of action. This proposed
research is significant because a new drug would be important in the chemotherapy of drug-resistant
schistosomiasis and likely be valuable in integrated control programs to curb this parasitic disease.
血吸虫病是一种由血吸虫属吸虫感染引起的热带寄生虫病。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Jonathan L Vennerstrom其他文献
Jonathan L Vennerstrom的其他文献
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{{ truncateString('Jonathan L Vennerstrom', 18)}}的其他基金
Leveraging RC-12 for Radical Cure of Plasmodium Vivax
利用 RC-12 根治间日疟原虫
- 批准号:
8430756 - 财政年份:2013
- 资助金额:
$ 62.56万 - 项目类别:
Increasing the Antischistosomal Selectivity of Aryl Hydantoins
提高芳基乙内酰脲的抗血吸虫选择性
- 批准号:
8374010 - 财政年份:2012
- 资助金额:
$ 62.56万 - 项目类别:
Increasing the Antischistosomal Selectivity of Aryl Hydantoins
提高芳基乙内酰脲的抗血吸虫选择性
- 批准号:
8523778 - 财政年份:2012
- 资助金额:
$ 62.56万 - 项目类别:
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