Structurally engineered furan fatty acids for the treatment of dyslipidemia and cardiovascular disease
Structurally engineered furan fatty acids for the treatment of dyslipidemia and cardiovascular disease
批准号:
10603408
负责人:
Francisco Jose Schopfer
金额:
$29.92万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-05-01 至 2025-04-30
关键词:
AccelerationAddressAdherenceAgonistAnimal ModelAnimalsAnti-Inflammatory AgentsAntiatherogenicAntiinflammatory EffectApolipoprotein EAreaAtherogenic DietAtherosclerosisBenchmarkingBiochemicalBiological AvailabilityBiological MarkersBlood VesselsCardiovascular DiseasesCardiovascular PathologyCardiovascular systemCessation of lifeCholesterolClinicalClinical ResearchCoenzyme ACombined Modality TherapyComplexDataDevelopmentDiabetes MellitusDiseaseDoseDrug KineticsDrug PrescriptionsDrug Side EffectsDyslipidemiasEngineeringEnzymesEventExposure toFDA approvedFatty AcidsFatty LiverFenofibrateFish OilsFoundationsFunctional disorderFuransFutureGlycolysisHalf-LifeHepaticHigh Density Lipoprotein CholesterolHigh Fat DietHypertensionHypertriglyceridemiaImmuneIncidenceIndividualInflammationInflammatoryInflammatory ResponseInsulinInsulin ResistanceInvestigationLeadLibrariesLipidsLipoproteinsLow-Density LipoproteinsMedicineMetabolicMetabolic DiseasesMetabolic dysfunctionMetabolic syndromeMetabolismMinorModelingMorbidity - disease rateMusNon-Insulin-Dependent Diabetes MellitusObesityOilsOmega-3 Fatty AcidsOutcomePathway AnalysisPatientsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPharmacology StudyPhasePhase II Clinical TrialsPlasmaPolypharmacyPropertyResearchResidual stateRiskRisk FactorsRodentRouteSeriesSolidSynthesis ChemistryTestingTherapeuticTissuesTranslationsTriglyceridesUnderserved Populationabsorptionanalytical methodbench-to-bedside translationblood glucose regulationcardiovascular disorder preventioncardiovascular risk factorcomorbiditycompliance behaviorcourse developmentdesigndiabetic patientdrug candidatedrug developmentexperiencefasting glucosefatty acid analogfatty acid metabolismfatty acid oxidationholistic approachimprovedin vivoinflammatory markerinterdisciplinary approachmarinemass spectrometermimeticsmortalitymouse modelnitroalkenenon-alcoholic fatty liver diseasenovelnovel strategiesnovel therapeutic interventionpharmacodynamic biomarkerpre-clinicalpreclinical developmentpreclinical studyprimary endpointresponserosuvastatinsecondary endpointstemsuccesssynergismtranscriptome sequencing
中文摘要
1项目概述
英文摘要
1 Project Summary
2 Cardiovascular risks in dyslipidemia patients are commonly controlled by lowering the LDL-C level using statins.
3 However, a significant residual cardiovascular risk persists in patients with additional concurrent risk factors such
4 as obesity, diabetes, insulin resistance, and elevated triglyceride-rich lipoproteins. Given the multifaceted
5 underlying pathology of cardiovascular disease, polypharmacy approaches are applied to target individual risk
6 factors but with limited success due to various drug side effects, lack of synergy, and low patient adherence.
7 Fish oils effectively lower hypertriglyceridemia, and omega-3 fatty acids-based treatments are approved by FDA
8 to treat this condition. We discovered a minor component of fish oil, also present in FDA-approved omega-3-
9 based drugs, that is more potent in eliciting these effects. Using a medicinal chemistry approach, we designed,
10 synthesized, tested, and optimized a series of compounds with improved metabolic stability and therapeutic
11 potency. The lead compound, FA-1011, demonstrated significant protection in a high-fat diet NAFLD mouse
12 model, reducing circulating cholesterol, triglycerides, hepatic steatosis, inflammatory markers caused by a
13 significant hepatic metabolic rewiring. The protective, anti-inflammatory effect and the improvement in circulating
14 lipid profile led us to hypothesize that FA-1011 could tackle the multifactorial cardiovascular disease by reducing
15 plaque formation, normalizing dyslipidemia, alleviating insulin resistance, and soliciting anti-inflammatory
16 responses. In particular, the hypothesis will be tested by pursuing the following Specific Aims:
17 Aim 1: Evaluate the absorption, distribution, and metabolism of FA-1011.
18 Aim 2: Define the protection of FA-1011 against atherosclerosis in ApoE–/– mice.
19 The multidisciplinary approach involved in the project including synthetic chemistry, mass spectrometer-based
20 analytics, and animal pharmacokinetics and pharmacology will definitively reveal the ADME, validate the anti-
21 atherosclerotic impact and characterize the modes of action of the lead compound FA-1011. The successful
22 outcomes of this project will result in a solid preclinical candidate ready for IND-enabling studies, and greatly
23 accelerate its translation to real clinical value for patients with excessive cardiovascular risk burden.
24 The team leading this effort is experienced and has participated in several preclinical and clinical studies (5
25 Phase I and 2 Phase II) in related disease areas. In addition, the team is supported by significant collaborators
26 and consultants to successfully execute the proposed research plan.
27
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会议论文
Structurally engineered N-acyl amino acids for the treatment of NASH
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批准号:10761044
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项目类别:
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资助金额:$29.35万
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财政年份:2023
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负责人:Francisco Jose Schopfer
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依托单位:
Predominant protective role in hepatic steatosis and obesity by fish oil-derived furans
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批准号:9904142
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项目类别:
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资助金额:$39.61万
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财政年份:2018
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负责人:Francisco Jose Schopfer
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依托单位:
Formation and metabolism of nitrated fatty acids
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批准号:10806470
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项目类别:
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资助金额:$1.03万
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财政年份:2017
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负责人:Francisco Jose Schopfer
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依托单位:
Formation and metabolism of nitrated fatty acids
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批准号:10796440
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项目类别:
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资助金额:$11.75万
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财政年份:2017
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负责人:Francisco Jose Schopfer
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依托单位:
Formation and metabolism of nitrated fatty acids
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批准号:10552005
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项目类别:
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资助金额:$39.75万
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财政年份:2017
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负责人:Francisco Jose Schopfer
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依托单位:
Formation and metabolism of nitrated fatty acids
-
批准号:10388616
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项目类别:
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资助金额:$39.49万
-
财政年份:2017
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负责人:Francisco Jose Schopfer
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依托单位:
Formation of Omega 3-Derived Electrophiles During Inflammation
-
批准号:8195180
-
项目类别:
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资助金额:$37.88万
-
财政年份:2011
-
负责人:Francisco Jose Schopfer
-
依托单位:
Formation of Omega 3-Derived Electrophiles During Inflammation
-
批准号:8891371
-
项目类别:
-
资助金额:$36.37万
-
财政年份:2011
-
负责人:Francisco Jose Schopfer
-
依托单位:
Formation of Omega 3-Derived Electrophiles During Inflammation
-
批准号:8514394
-
项目类别:
-
资助金额:$36.37万
-
财政年份:2011
-
负责人:Francisco Jose Schopfer
-
依托单位:
Formation of Omega 3-Derived Electrophiles During Inflammation
-
批准号:8311659
-
项目类别:
-
资助金额:$37.5万
-
财政年份:2011
-
负责人:Francisco Jose Schopfer
-
依托单位:
Formation of Omega 3-Derived Electrophiles During Inflammation
-
批准号:8704319
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项目类别:
-
资助金额:$36.37万
-
财政年份:2011
-
负责人:Francisco Jose Schopfer
-
依托单位:
海外基金