Project Grant R43AR081768

Award Date 7/1/22
Completion Date 8/31/23
Dollars Obligated $548K
Federal Grant Program
93.846
Assistance Type
Project Grant
Place of Performance
Exton, PA 19341, USA
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NOVEL 5-HT7 ANTAGONISTS FOR THE TREATMENT OF PRURITUS - PROJECT SUMMARY (ABSTRACT) EVIDENCE SUPPORTING SEROTONIN (5-HT) AS A CONTRIBUTING FACTOR TO THE SEVERITY OF PRURITUS HAS BEEN WIDELY REPORTED. ELEVATED LEVELS OF 5-HT HAVE BEEN REPORTED IN PATIENTS WITH ATOPIC DERMATITIS AND CHRONIC ECZEMA, THUS SUPPORTING 5-HT AS A CONTRIBUTING FACTOR. ADDITIONALLY, 5-HT INVOKES DOSE-DEPENDENT SCRATCHING WHEN ADMINISTERED VIA INTRADERMAL INJECTION IN RODENTS. STUDIES HAVE DEMONSTRATED THAT 5-HT INDUCES SCRATCHING SENSATIONS BY ACTIVATING A SUBSET OF RECEPTORS. SUBSTANTIAL EVIDENCE SUPPORTS A ROLE OF PERIPHERAL 5-HT7 RECEPTORS IN CHRONIC ITCH VIA OPENING OF THE TRPA1 CHANNEL. OPENING OF THE TRPA1 CHANNEL IS REPORTED TO BE REQUIRED FOR THE MANIFESTATION OF CHRONIC PRURITUS. 5-HT7 IS CO-EXPRESSED WITH TRPA1 IN A SUBSET OF PRIMARY AFFERENT SENSORY NEURONS THAT INNERVATE THE SKIN. WHEN 5-HT7 WAS ACTIVATED WITH EITHER 5-HT OR A HIGHLY SELECTIVE 5-HT7 AGONIST (LP-44) IT TRIGGERS NEURONAL EXCITATION VIA CALCIUM FLUX THRU THE TRPA1 CHANNEL IN A CYCLIC AMP DEPENDENT MATTER. THE INVOLVEMENT OF 5-HT7 IN PRURITUS WAS SUPPORTED IN VIVO AS INTRADERMAL ADMINISTRATION OF LP-44 INTO THE CHEEK OF MICE EVOKED SIGNIFICANT SCRATCHING BEHAVIOR THAT WAS ATTENUATED VIA PHARMACOLOGICAL BLOCKADE WITH A SELECTIVE 5-HT7 ANTAGONIST (SB-269970). 5-HT AND LP-44 INDUCED SCRATCHING WAS ALSO ATTENUATED IN EITHER 5-HT7 OR TRPA1 KNOCK-OUT MICE. ADDITIONALLY, 5-HT7 AND TRPA1 KNOCK-OUT MICE DISPLAYED REDUCED SCRATCHING AND SKIN LESION SEVERITY IN AN ATOPIC DERMATITIS MODEL (MC903 INDUCED) WHERE 5-HT LEVELS WERE SIGNIFICANTLY INCREASED AT THE AFFECTED SITE. THIS DATA SUGGESTS THAT A 5-HT7 ANTAGONIST COULD BE USEFUL FOR THE TREATMENT OF PRURITUS. WE HAVE CHOSEN 6 HIGHLY POTENT, SELECTIVE 5-HT7 ANTAGONISTS THAT DISPLAY PERIPHERALLY RESTRICTED PHARMACOKINETIC (PK), GOOD DERMAL PENETRATION/PERMEABILITY AND SAFE PRELIMINARY ADMET PROFILES. WE HYPOTHESIZE THAT OUR NOVEL 5-HT7 ANTAGONISTS WILL ATTENUATE SCRATCHING IN MURINE MODELS OF PRURITUS (MC903) AND PROVIDE A NOVEL MECHANISM FOR TREATING PRURITUS. WE WILL PURSUE A MULTIPRONGED APPROACH FOCUSED ON IDENTIFYING NOVEL LEAD COMPOUNDS SUITABLE FOR ADVANCED IN VIVO EFFICACY STUDIES.

Posted 6/24/22, 12:00 AM