Topical selective T-type blockers for the treatment of pruritus
局部选择性 T 型阻滞剂治疗瘙痒
基本信息
- 批准号:9907737
- 负责人:
- 金额:$ 22.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2021-02-28
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAction PotentialsAcuteAddressAdultAdverse effectsAffectAmericanAnti-inflammatoryAntipruritic EffectAntipruriticsAutoimmune ResponsesBehaviorBlood CirculationC FiberCD4 Positive T LymphocytesCalciumCalcium Channel BlockersCardiotoxicityCellsChemicalsClinical ResearchCytochromesDataDermatologicDermatologyDevelopmentDiseaseDoseEsthesiaExhibitsExperimental Autoimmune EncephalomyelitisFamilyFire - disastersFunctional disorderGoalsHealthHidradenitis SuppurativaHistamineHumanHuman GenomeImmuneImmunologyIn VitroInflammationInflammatoryInvestigational New Drug ApplicationLeadLegal patentLightLiverMechanoreceptorsMediatingMetabolicMetabolismMicrosomesModelingMusNamesNerveNerve EndingsNeuronsNitrogenNociceptionOral AdministrationPatientsPatternPerceptionPeripheralPeripheral Blood Mononuclear CellPermeabilityPharmaceutical ChemistryPharmacologyPhaseProductionPropertyProtein IsoformsPrurigoPruritusResistanceRiskRodentRoleSafetyShapesSkinSmall Business Innovation Research GrantStimulusStructureSymptomsSynapsesT-LymphocyteT-Type Calcium ChannelsTNF geneTherapeuticTimeTopical applicationTouch sensationToxic effectWorkabsorptionanalogassociated symptombasechronic inflammatory skinchronic itchcytokinedesignimprovedin vivoin vivo Modelinhibitor/antagonistkeratinocyte differentiationmacrophagenext generationnovelnovel therapeuticsoff-patentpediatric patientspre-clinicalpreclinical studypublic health relevanceresponseskin disorder
项目摘要
Project Summary / Abstract: Pruritus, also called itch, is the most frequent dermatological symptom in the US
with up to 20% of Americans being affected. Pruritic stimuli are detected by a subset of nociceptive neurons,
pruriceptors, which fire action potential in response to peripheral activation by TH2 or TH17 molecules induced
by chronic inflammatory skin diseases such as ichthyosis, prurigo nodularis, and hidradenitis suppurativa. T-type
calcium channels contribute to the firing behavior of itch-sensing neurons in synaptic skin nerve terminals and
have recently been discovered to mediate calcium entry in immune cells. This T-type calcium channel expression
pattern is consistent with their critical roles at detecting itch sensations associated with skin inflammatory
diseases. Preliminary work has enabled us to formulate the central hypothesis that topical inhibition of the three
T-type channel isoforms in the skin will silence action potential (AP) discharge of itch Aδ and C-fibers induced
by pruritogenic and inflammatory cytokines, will directly reduce the release of these cytokines by TH2 or TH17
cells, and will lead to improved efficacy and limited systemic exposure, together reducing the risk of adverse
effects compared to systemic treatments. Our hypothesis is strongly supported by our experimental findings.
First, our lead compound, DX416, is a potent inhibitor of the three T-type channels, Cav3.1, Cav3.2, and Cav3.3
at sub-micromolar levels. Second, treatment with DX416 does not induce psychoactivity in rodents but
profoundly reduces histamine-evoked itch in mice after intradermal administration. Third, we discovered DX401,
a T-type blocker that reduces histamine-evoked itch after oral administration. Fourth, we show for the first time
that these two Cav3s blockers, DX416 and DX401, significantly reduce the release of TH2 pruritic cytokine, IL-
31, after human peripheral blood mononuclear cell (PBMC) activation, and TH17-synergizing cytokine, TNFα, by
activated macrophages. The overall goal of this collaborative effort between DermaXon’s experts in medicinal
chemistry, immunology, and dermatology is to demonstrate the technical feasibility of developing inhibitors of
skin T-type channels as novel therapeutics for the topical treatment of pruritus associated with inflammatory skin
diseases. Our objectives in this proposal are: Aim 1) complete the optimization of our first topical T-type lead
inhibitor DX416, based on our previously designed chemotypes and characterize their Cav3s activity and
selectivity; Aim 2) compare the effect of four Cav3s blockers selected in SA1 on proinflammatory and
pruritogenic cytokine release by activated immune cells, and assess their safety; Aim 3) compare the anti-pruritic
efficacy after intra-dermal administration of two T-type channels inhibitors selected in Aim 2 using the histamine-
evoked acute itch and the dry skin chronic itch in vivo models. The identification of lead compounds that are
active in preclinical acute and chronic itch models will set the stage for a next generation of topical pruritus
therapeutics to be used in both adult and pediatric patients suffering from itch associated with inflammatory skin
diseases, and will support development of a novel therapeutic topical treatment.
项目摘要/摘要:瘙痒症,又称瘙痒,是美国最常见的皮肤病症状
项目成果
期刊论文数量(0)
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Fanny Astruc Diaz其他文献
Fanny Astruc Diaz的其他文献
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