Praeventix LLC

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.