Development of Novel Second Generation Anti-inflammatory Substrate-selective p38 MAP Kinase Inhibitors as Therapy for Acute Respiratory Distress Syndrome
开发新型第二代抗炎底物选择性 p38 MAP 激酶抑制剂治疗急性呼吸窘迫综合征
基本信息
- 批准号:10535453
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVAcute Lung InjuryAcute Respiratory Distress SyndromeAddressAffectAffinityAnti-Inflammatory AgentsAntiinflammatory EffectAspartateAwardBindingBinding ProteinsBiologicalBiological AssayBiological SciencesBleomycinBlood VesselsCOVID-19COVID-19/ARDSCatalytic DomainCell modelCellsCessation of lifeChemicalsChronic lung diseaseClinicClinical TrialsCollaborationsComplicationComputer AssistedComputersDatabasesDeath RateDevelopmentDiabetes MellitusDockingDoseDrug DesignDrug KineticsEffectivenessEndotheliumExhibitsFeverFormulationFundingFutureGenerationsGlutamatesGoalsHeart DiseasesHumanHypertensionHyperthermiaIn VitroInduced HyperthermiaInfectionInflammationInflammatoryInfluenzaInjuryLeadLegal patentLicensingLungMapsMarylandMitogen-Activated Protein Kinase InhibitorMitogen-Activated Protein KinasesMitogensModelingModificationMolecularMonkeysMorbidity - disease rateMusObesityOutcomePathogenicityPathway interactionsPatientsPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPharmacodynamicsPharmacy SchoolsPhasePhosphotransferasesPlasmaPreclinical TestingPreparationProcessProgram DevelopmentPropertyProtective AgentsProtein KinaseProtein phosphataseRPS6KA5 geneRattusResearch PersonnelRisk FactorsSafetyServicesSignal TransductionSiteSolubilitySpecificitySurface Plasmon ResonanceSurvivorsTestingTherapeuticThrombinToxic effectUniversitiesVeteransVirusWorkanalogaqueouscandidate identificationcytokinedesigndisabilitydrug candidatedrug developmentefficacy testingepithelial injuryhuman old age (65+)improvedin vivoin vivo evaluationinhibitorkinase inhibitorlung injurymortalitymouse modelmultimodalitynovelnovel therapeuticsp38 Mitogen Activated Protein Kinasepatient populationpharmacologicphosphoproteomicsprotective effectpulmonary artery endothelial cellreceptorreceptor bindingresearch clinical testingrespiratory virussafety studyscaffoldscreeningstress activated protein kinasetherapeutic candidatetherapeutic target
项目摘要
Acute Respiratory Distress Syndrome (ARDS) affects ~190,000 patients and causes ~75,000 deaths per year
in the U.S.A. ARDS has a mortality rate of ~40% and causes significant morbidity in survivors. Respiratory
viruses, including influenza and now Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), are
important causes of ARDS with limited therapeutic options. The VA patient population has many of the risk
factors for having poor outcomes with ARDS, including older age, obesity, hypertension, diabetes, and chronic
lung and heart disease. There are no currently available pharmacologic therapies proven to be effective in
ARDS. To address this need, we developed a novel class of substrate- and function-selective p38 mitogen-
activated protein kinases (MAPK) inhibitors with anti-inflammatory and endothelial-barrier stabilizing activity.
Compared with conventional p38 catalytic inhibitors that block all downstream signaling including anti-
inflammatory pathways, our novel compounds target one of the substrate docking sites and therefore only
block certain p38-dependent processes. Together with my co-investigators, Drs. Shapiro, MacKerell, and
Fletcher, we used computer-aided drug design (CADD) to identify a lead compound, UM101, that binds a
pocket near the ED substrate docking site on p38a and exhibits a unique profile of biological activities. We
developed a second-generation analog, SF7044, with greater solubility and improved endothelial barrier-
stabilizing, anti-inflammatory, and lung-protective activities. We are currently collaborating with Gen1e Life
Sciences, LLC, which licensed the patents for these compounds, completed preclinical testing and began
clinical testing of SF7044. During our current Merit Award, we identified and screened 200 additional
compounds targeted to the same substrate docking site as UM101 using a refined CADD strategy. We
identified four new lead compounds with superior endothelial barrier stabilizing activity and p38a-binding
compared with UM101 and SF7044 and distinct anti-inflammatory effect profiles, but poor solubility. In vivo
testing in a mouse model will require reformulation or chemical modification of these new lead compounds to
improve solubility (like UM101). The overall objective of this renewal is to use the same strategy as used for
development of SF7044 to design, synthesize, and characterize second-generation analogs of the four new
lead compounds with improved activity and drug-like properties. Since the new lead compounds have greater
endothelial-stabilizing activity and p38a-binding than either UM101 or SF7044 we expect to develop second-
generation analogs with substantially improved lung-protective activity. We will utilize CADD and medicinal
chemistry principles, protein binding assays and human cell and mouse models of ALI:
1. Design and synthesize at least 20 analogs of each the 4 newly discovered lead compounds to improve
p38a-binding and drug-like properties.
2. Analyze the second-generation analogs for target binding and biological activities.
3. Analyze toxicity and effectiveness of the most active second-generation analogs in mouse models of the
exudative (LPS/hyperthermia) and fibroproliferative (bleomycin) phases of ARDS.
4. Evaluate new compounds for off-target effects
At the conclusion of this work, we will have developed second generation analogs of novel non-catalytic
p38α inhibitors with improved efficacy and safety profiles in mouse lung injury models to provide a pipeline
of new compounds that are ready for advanced preclinical testing prior to clinical testing in ARDS.
急性呼吸窘迫综合征(ARDS)每年影响约19万患者,导致约7.5万人死亡
项目成果
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JEFFREY D HASDAY其他文献
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{{ truncateString('JEFFREY D HASDAY', 18)}}的其他基金
Development of Novel Second Generation Anti-inflammatory Substrate-selective p38 MAP Kinase Inhibitors as Therapy for Acute Respiratory Distress Syndrome
开发新型第二代抗炎底物选择性 p38 MAP 激酶抑制剂治疗急性呼吸窘迫综合征
- 批准号:
10367545 - 财政年份:2018
- 资助金额:
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Hyperthermia-augmented epithelial apoptosis and acute lung injury
热疗增强上皮细胞凋亡和急性肺损伤
- 批准号:
8542278 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Hyperthermia-augmented epithelial apoptosis and acute lung injury
热疗增强上皮细胞凋亡和急性肺损伤
- 批准号:
8974334 - 财政年份:2013
- 资助金额:
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Hyperthermia-augmented epithelial apoptosis and acute lung injury
热疗增强上皮细胞凋亡和急性肺损伤
- 批准号:
8721706 - 财政年份:2013
- 资助金额:
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Novel Mechanisms of Smooth Muscle Beta2-receptor Regulation Relevant to Asthma
与哮喘相关的平滑肌β2受体调节新机制
- 批准号:
8661247 - 财政年份:2010
- 资助金额:
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The contribution of heat shock/stress pathways to acute lung injury
热休克/应激途径对急性肺损伤的影响
- 批准号:
7264065 - 财政年份:2007
- 资助金额:
-- - 项目类别:
The contribution of heat shock/stress pathways to acute lung injury
热休克/应激途径对急性肺损伤的影响
- 批准号:
7386621 - 财政年份:2007
- 资助金额:
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The contribution of heat shock/stress pathways to acute lung injury
热休克/应激途径对急性肺损伤的影响
- 批准号:
7586229 - 财政年份:2007
- 资助金额:
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The contribution of heat shock/stress pathways to acute lung injury
热休克/应激途径对急性肺损伤的影响
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7780051 - 财政年份:2007
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Mechanisms of HSF1-mediated Repression of TNF-alpha
HSF1 介导的 TNF-α 抑制机制
- 批准号:
6875575 - 财政年份:2004
- 资助金额:
-- - 项目类别:
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