New Approach to Atopic Dermatitis

PROJECT SUMMARYCurrent thinking has provided substantial support for the hypothesis that primary afferent and neuraxial neurogenic peptide receptors play a prominent role in pruritic pathologiesOf equal interestis the growing appreciation that receptor signaling may also play a facilitatory role in inflammation in disease statesThe confluence of these phenomena emphasize the likely importance of peripherally acting receptors in regulating aberrant sensations in pruritic states including atopic dermatitisADOur data and literature support a link between neurogenic peptides to signaling by the Mas related GPCR family and that this signaling is governed by the transient receptor potential cation channelmember ATRPAAccordinglyfunctional TRPAantagonists are expected to be key regulators of conditions like AD in terms of both pruritus and cutaneous inflammationThe goal of this application is to optimize one or more small molecule antagonists of the TRPAchannel as a probe to study in vivo efficacy in animal models of ADIn this proposalthe drug discovery team at Epigen Biosciences Incwill conduct a lead identification plan to identify novel small molecules with suitable drug like properties for pre clinical evaluation of efficacy in preclinical models of atopic dermatitisNew compounds will be optimized for metabolic stabilityCompounds with adequate in vitro profile will be studied at University of California San DiegoUCSDin mice to identify compounds that prevent scratching responsesA lead compound will be further assessed in a preliminary model of atopic dermatitis for its ability to block behavioral responses and suppress preliminary markers of inflammationStudies in atopic dermatitis will provide data on measures of dermal integrityepidermal water loss and skin thicknesshistopathology and measures of cytokine levelsprotein and RNA from qPCRThese data are expected to demonstrate the utility of novel TRPAantagonists in atopic dermatitis and support a lead optimization program as a prelude to commercial developmentThe lead compound will be then assessed for drug profile riskcytochrome Pand hERG inhibitionto guide future work Narrative The objective is to discover novel antagonists of the transient receptor potential cation channelmember ATRPAand evaluate a lead for efficacy in pre clinical animal models of atopic dermatitisa disease which causes significant disability and reduces quality of life