2025
Chapter 49 Phase 0 & window of opportunity clinical trials
Reddy A, Bansal U, Lerner S. Chapter 49 Phase 0 & window of opportunity clinical trials. 2025, 249-253. DOI: 10.1016/b978-0-323-90186-4.00009-2.Peer-Reviewed Original ResearchExploratory investigational new drugClinical trialsPhase 1 clinical trialPreclinical animal studiesFood and Drug AdministrationInvestigational new drugOn-target effectsPhase 0 studiesDrug pharmacokineticsDrug efficacyDrug AdministrationAnimal studiesOncology drugsDrug trialsSuboptimal pharmacological propertiesNew drugsDrug approvalDrugDrug approval processCosts associated with drug developmentPharmacological propertiesDrug safetyTrialsDrug developmentTherapeutic areas
2024
Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid
Papini C, Ullah I, Ranjan A, Zhang S, Wu Q, Spasov K, Zhang C, Mothes W, Crawford J, Lindenbach B, Uchil P, Kumar P, Jorgensen W, Anderson K. Proof-of-concept studies with a computationally designed Mpro inhibitor as a synergistic combination regimen alternative to Paxlovid. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2320713121. PMID: 38621119, PMCID: PMC11046628, DOI: 10.1073/pnas.2320713121.Peer-Reviewed Original ResearchConceptsDirect-acting antiviralsSARS-CoV-2Lack of off-target effectsIn vitro pharmacological profileTreatment of patientsDevelopment of severe symptomsPharmacological propertiesDrug-drug interactionsSARS-CoV-2 infectionProof-of-concept studySARS-CoV-2 M<sup>pro</sup>.Combination regimenImmunocompromised patientsLead compoundsSARS-CoV-2 main proteaseOral doseActive drugTreat infectionsPharmacological profileSARS-CoV-2 MPotential preclinical candidateOff-target effectsPatientsComplete recoveryCapsule formulationEffectiveness of Two New Endochin-like Quinolones, ELQ-596 and ELQ-650, in Experimental Mouse Models of Human Babesiosis
Vydyam P, Chand M, Pou S, Winter R, Liebman K, Nilsen A, Doggett J, Riscoe M, Mamoun C. Effectiveness of Two New Endochin-like Quinolones, ELQ-596 and ELQ-650, in Experimental Mouse Models of Human Babesiosis. ACS Infectious Diseases 2024, 10: 1405-1413. PMID: 38563132, PMCID: PMC11127568, DOI: 10.1021/acsinfecdis.4c00143.Peer-Reviewed Original ResearchConceptsRadical cureEndochin-like quinolonesAgent of human malariaLethal infection modelTreatment of human babesiosisLow toxicity profileExperimental mouse modelImmunocompetent miceImmunocompromised miceFavorable pharmacological propertiesHuman malariaToxicity profileChronic modelHuman babesiosisAnimal modelsInfection modelPharmacological limitationsActivity in vitroPharmacological propertiesReduce infectionQuinolonesMiceMitochondrial electron transport chainFavorable physicochemical propertiesMonotherapy
2022
Modulators of ASIC1a and its potential as a therapeutic target for age-related diseases
Zhou R, Liang H, Hu W, Ding J, Li S, Chen Y, Zhao Y, Lu C, Chen F, Hu W. Modulators of ASIC1a and its potential as a therapeutic target for age-related diseases. Ageing Research Reviews 2022, 83: 101785. PMID: 36371015, DOI: 10.1016/j.arr.2022.101785.Peer-Reviewed Original ResearchConceptsAcid-sensing ion channel 1aAge-related diseasesTherapeutic targetPotential therapeutic targetMost age-related diseasesIon channel 1aNovel drug targetsEffective drugsMultiple organsPathophysiological processesChannel 1aDiseaseChannel family membersPharmacological propertiesImproved treatmentSuch diseasesTissue degenerationCellular apoptosisTreatmentDrug targetsFamily membersPhysiological functionsUrgent needWorldwide populationIschemia
2021
Immunomodulatory functions of TRPM7 and its implications in autoimmune diseases
Liang H, Chen Y, Wei X, Ma G, Ding J, Lu C, Zhou R, Hu W. Immunomodulatory functions of TRPM7 and its implications in autoimmune diseases. Immunology 2021, 165: 3-21. PMID: 34558663, DOI: 10.1111/imm.13420.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutoimmune DiseasesAutoimmunityBiomarkersDisease SusceptibilityDrug DevelopmentGene Expression RegulationHumansImmune SystemImmunomodulationIon Channel GatingOrgan SpecificityProtein Kinase InhibitorsProtein Serine-Threonine KinasesSignal TransductionStructure-Activity RelationshipTRPM Cation ChannelsConceptsAutoimmune diseasesRole of TRPM7New treatment targetsPotential therapeutic targetReceptor ion channelsImmune toleranceRheumatoid arthritisMultiple sclerosisSystemic disordersBody of evidenceImmune cellsCytokine secretionImmunoreactive substancesFunctional damageImmunomodulatory functionsTherapeutic targetTreatment targetsDiseaseEffective interventionsPharmacological propertiesOne-tissueTRPM7Physiologic conditionsInappropriate responsesCell migration
2020
Trends in Therapeutic Conjugates: Bench to Clinic
Rudra A, Li J, Shakur R, Bhagchandani S, Langer R. Trends in Therapeutic Conjugates: Bench to Clinic. Bioconjugate Chemistry 2020, 31: 462-473. PMID: 31990184, DOI: 10.1021/acs.bioconjchem.9b00828.Peer-Reviewed Original Research
2019
Enhancement of human iPSC-derived cardiomyocyte maturation by chemical conditioning in a 3D environment
Huang CY, Peres Moreno Maia-Joca R, Ong CS, Wilson I, DiSilvestre D, Tomaselli GF, Reich DH. Enhancement of human iPSC-derived cardiomyocyte maturation by chemical conditioning in a 3D environment. Journal Of Molecular And Cellular Cardiology 2019, 138: 1-11. PMID: 31655038, DOI: 10.1016/j.yjmcc.2019.10.001.Peer-Reviewed Original ResearchConceptsInsulin-like growth factor-1HiPSC-CMsSarcoplasmic reticulum functionGrowth factor-1Pluripotent stem cell-derived cardiomyocytesStem cell-derived cardiomyocytesCell-derived cardiomyocytesAdult cardiac phenotypeTDI treatmentContractile propertiesElectrophysiological propertiesThyroid hormonesCardiac phenotypeAdult myocardiumCardiac microtissuesPharmacological propertiesRecapitulate aspectsFactor 1Gene expression profilesHuman iPSCBiochemical factorsImmature stateMyocardiumStem cellsPluripotent stem cellsMolecular constituents and localization of the ionotropic GABA receptor complex in vivo
Tomita S. Molecular constituents and localization of the ionotropic GABA receptor complex in vivo. Current Opinion In Neurobiology 2019, 57: 81-86. PMID: 30784980, PMCID: PMC6629498, DOI: 10.1016/j.conb.2019.01.017.Peer-Reviewed Original ResearchConceptsNative receptor complexReceptor complexPore-forming subunitMolecular constituentsNew mechanistic insightsProtein familySubunit assemblyMajor molecular constituentsProperties of GABASynaptic localizationIonotropic GABA receptorsPrimary neuronsMechanistic insightsGABA receptor complexNative GABAReceptor regulationGABA receptorsNeuroligin-2R complexesGABAFast inhibitionPharmacological propertiesComplexesLocalizationSubunits
2017
BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells
Sun B, Fiskus W, Qian Y, Rajapakshe K, Raina K, Coleman KG, Crew AP, Shen A, Saenz DT, Mill CP, Nowak AJ, Jain N, Zhang L, Wang M, Khoury JD, Coarfa C, Crews CM, Bhalla KN. BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells. Leukemia 2017, 32: 343-352. PMID: 28663582, DOI: 10.1038/leu.2017.207.Peer-Reviewed Original ResearchConceptsMantle cell lymphoma cellsMCL cellsCell lymphoma cellsARV-825ARV-771Lymphoma cellsGreater survival improvementSuperior preclinical activityCDK4/6 inhibitor palbociclibNuclear factor-κB (NF-κB) target genesExtraterminal protein inhibitorSurvival improvementInhibitor palbociclibPreclinical activityCDKN1A/p21Inhibitor treatmentSuperior pharmacological propertiesVivo growthCyclin D1Pharmacological propertiesProtein expressionMore apoptosisVivo evaluationIncomplete inhibitionC-Myc
2013
Perioperative management of antiplatelet therapy
Oprea AD, Popescu WM. Perioperative management of antiplatelet therapy. British Journal Of Anaesthesia 2013, 111: i3-i17. PMID: 24335397, DOI: 10.1093/bja/aet402.Peer-Reviewed Original ResearchConceptsCardiovascular thrombotic eventsAntiplatelet agentsAntiplatelet medicationsThrombotic eventsPerioperative antiplatelet managementFirst-line therapyPreferred therapeutic strategyNovel antiplatelet drugsRisk stratification analysesDifferent pharmacological propertiesAntiplatelet therapyCardiovascular eventsPerioperative managementSurgical bleedingAntiplatelet drugsAntiplatelet managementTherapeutic pathwaysTherapeutic strategiesStratification analysisInterventional proceduresPerioperative teamPharmacokinetic propertiesPharmacological propertiesMajor causeMedications
2012
Phospholipase C mediates (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-, but not lysergic acid diethylamide (LSD)-elicited head bobs in rabbit medial prefrontal cortex
Schindler EA, Harvey JA, Aloyo VJ. Phospholipase C mediates (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-, but not lysergic acid diethylamide (LSD)-elicited head bobs in rabbit medial prefrontal cortex. Brain Research 2012, 1491: 98-108. PMID: 23123701, PMCID: PMC3559188, DOI: 10.1016/j.brainres.2012.10.057.Peer-Reviewed Original ResearchMeSH KeywordsAmphetaminesAnimalsBehavior, AnimalCerebral CortexEnzyme ActivationEnzyme InhibitorsEstrenesHallucinogensHead MovementsHydrolysisLysergic Acid DiethylamideMaleMicroinjectionsPhosphatidylinositolsPrefrontal CortexPyrrolidinonesRabbitsReceptor, Serotonin, 5-HT2ASerotonin AntagonistsSerotonin Receptor AgonistsSignal TransductionType C PhospholipasesConceptsMedial prefrontal cortexLysergic acid diethylamidePI hydrolysisReceptor antagonistPrefrontal cortexDimethoxy-4Acid diethylamidePhospholipase CDistinct pharmacological propertiesEffects of hallucinogensActivation of PLCTissue prismsSerotonergic receptorsReceptor mechanismsPhosphatidylinositol hydrolysisPharmacological propertiesIntracellular mechanismsPLC inhibitorPLC activationHead bobsTrien-17Receptor signalsHallucinogensNovel findingsAntagonistGabra5-gene haplotype block associated with behavioral properties of the full agonist benzodiazepine chlordiazepoxide
Clément Y, Prut L, Saurini F, Mineur Y, Le Guisquet A, Védrine S, Andres C, Vodjdani G, Belzung C. Gabra5-gene haplotype block associated with behavioral properties of the full agonist benzodiazepine chlordiazepoxide. Behavioural Brain Research 2012, 233: 474-482. PMID: 22677273, DOI: 10.1016/j.bbr.2012.05.041.Peer-Reviewed Original ResearchMeSH KeywordsAdaptation, PsychologicalAnimalsBehavior, AnimalBenzodiazepinesCarrier ProteinsCerebral CortexChlordiazepoxideDose-Response Relationship, DrugGene Expression RegulationHaplotypesHippocampusMaleMaze LearningMembrane ProteinsMiceMice, Inbred C57BLMice, Mutant StrainsMotor ActivityMutationReaction TimeReceptors, GABA-ARNA, MessengerRotarod Performance TestSpace Perception
2010
Effect of capsaicin on potassium conductance and electromotility of the guinea pig outer hair cell
Wu T, Song L, Shi X, Jiang Z, Santos-Sacchi J, Nuttall A. Effect of capsaicin on potassium conductance and electromotility of the guinea pig outer hair cell. Hearing Research 2010, 272: 117-124. PMID: 21044673, PMCID: PMC3387680, DOI: 10.1016/j.heares.2010.10.010.Peer-Reviewed Original ResearchConceptsOuter hair cellsTRPV-1 channelsHair cellsPrimary sensory neuronsEffects of capsaicinGuinea pig outer hair cellsSensory neuronsPharmacological actionsCapsaicinPotassium conductancePotent blockerPharmacological propertiesDirect actionNovel actionCochlear amplificationK conductanceAuditory effectsClassic activatorAuditory receptionCellsNociceptionElectromotilityBlockersNew findingsNeuronsDevelopment of effective PET and SPECT imaging agents for the serotonin transporter: has a twenty-year journey reached its destination?
Huang Y, Zheng MQ, Gerdes JM. Development of effective PET and SPECT imaging agents for the serotonin transporter: has a twenty-year journey reached its destination? Current Topics In Medicinal Chemistry 2010, 10: 1499-526. PMID: 20583995, DOI: 10.2174/156802610793176792.Peer-Reviewed Original ResearchConceptsChemical scaffoldsPositron emission tomographySerotonin transporterTwenty-year journeyImaging tracerFunction of SERTRelated compoundsNon-specific bindingSingle photon emissionRadiotracer developmentSpecific binding signalsPromising radiotracerAlzheimer's diseaseEmission tomographyNeurodegenerative disordersNeuropsychiatric disordersSPECT radiotracerSubstance abusePharmacological propertiesDiseaseScaffoldsTerms of tissueSPECTDiarylsulfidesVivo
2006
Optimization of pyrimidinyl- and triazinyl-amines as non-nucleoside inhibitors of HIV-1 reverse transcriptase
Thakur VV, Kim JT, Hamilton AD, Bailey CM, Domaoal RA, Wang L, Anderson KS, Jorgensen WL. Optimization of pyrimidinyl- and triazinyl-amines as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorganic & Medicinal Chemistry Letters 2006, 16: 5664-5667. PMID: 16931015, DOI: 10.1016/j.bmcl.2006.08.037.Peer-Reviewed Original ResearchConceptsHIV-1 reverse transcriptaseNon-nucleoside inhibitorsAnti-viral activityReverse transcriptasePharmacological propertiesInhibitorsTranscriptaseNM rangeNNRTIPharmacological activation and inhibition of Slack (Slo2.2) channels
Yang B, Gribkoff VK, Pan J, Damagnez V, Dworetzky SI, Boissard CG, Bhattacharjee A, Yan Y, Sigworth FJ, Kaczmarek LK. Pharmacological activation and inhibition of Slack (Slo2.2) channels. Neuropharmacology 2006, 51: 896-906. PMID: 16876206, DOI: 10.1016/j.neuropharm.2006.06.003.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnti-Infective Agents, LocalBepridilBithionolCalcium Channel BlockersCell Line, TransformedDose-Response Relationship, DrugDose-Response Relationship, RadiationElectric StimulationEnzyme ActivationEnzyme InhibitorsHumansMembrane PotentialsOocytesPatch-Clamp TechniquesPotassium Channels, Calcium-ActivatedQuinidineTransfectionXenopusConceptsSlack channelsConcentration-dependent mannerIschemic injuryPharmacological activationKNa channelsMammalian brainFiring ratePharmacological propertiesChannel subunitsReversible increaseChannel activityCell linesBepridilHEK cellsRobust activatorNeuronsStable cell linesInhibitionExcised patchesXenopus oocytesPresent studyBithionolChannel openingSpecific roleMembrane patches
2005
Pharmacological properties of neuronal TTX-resistant sodium channels and the role of a critical serine pore residue
Leffler A, Herzog RI, Dib-Hajj SD, Waxman SG, Cummins TR. Pharmacological properties of neuronal TTX-resistant sodium channels and the role of a critical serine pore residue. Pflügers Archiv - European Journal Of Physiology 2005, 451: 454-463. PMID: 15981012, DOI: 10.1007/s00424-005-1463-x.Peer-Reviewed Original Research
2003
Synthesis and affinity of a possible byproduct of electrophilic radiolabeling of [123I]IBZM
Baldwin R, Fu X, Kula N, Baldessarini R, Amici L, Innis R, Tamagnan G. Synthesis and affinity of a possible byproduct of electrophilic radiolabeling of [123I]IBZM. Bioorganic & Medicinal Chemistry Letters 2003, 13: 4015-4017. PMID: 14592497, DOI: 10.1016/j.bmcl.2003.08.063.Peer-Reviewed Original ResearchPhenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito
Akar FG, Wu RC, Deschenes I, Armoundas AA, Piacentino V, Houser SR, Tomaselli GF. Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito. AJP Heart And Circulatory Physiology 2003, 286: h602-h609. PMID: 14527940, DOI: 10.1152/ajpheart.00673.2003.Peer-Reviewed Original ResearchConceptsTransient outwardPhenotypic differencesKv channel-interacting proteinsIndependent transient outwardChannel-interacting proteinsProtein chemical techniquesSteady-state inactivationCanine ventricular myocytesWestern blot analysisElectrical remodelingChannel subunit genesMonoexponential time coursePharmacological sensitivityVentricular repolarizationCardiac diseaseElectrophysiological roleCanine ventricularHuman cardiac diseasePosttranslational modificationsVentricular myocytesSubunit genePharmacological propertiesDiseased heartPhenotypic propertiesOxidative stressComparative physiological and serotoninergic properties of pulvinar neurons in the monkey, cat and ferret
Monckton J, McCormick D. Comparative physiological and serotoninergic properties of pulvinar neurons in the monkey, cat and ferret. Thalamus & Related Systems 2003, 2: 239-252. DOI: 10.1016/s1472-9288(03)00022-0.Peer-Reviewed Original ResearchApplication of serotoninThalamocortical neuronsLow-threshold Ca2Pulvinar neuronsThreshold Ca2Hyperpolarization-activated cation currentSingle spike activityBasic electrophysiological propertiesDistinct firing modesProminent hyperpolarizationMembrane potassium conductanceSerotoninergic propertiesSignificant species-dependent differencesSpike activityCation currentMonkey neuronsElectrophysiological propertiesPotassium conductanceNeuronsPharmacological propertiesSerotoninMonkeysCatsPulvinarSpecies-dependent differences
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