Guanidinium Derivatives for the Treatment of Ocular Pain

DESCRIPTION provided by applicant The absence of safe effective strategies for the management of ocular pain is motivating the development of a novel topical drug suitable for patient self administration Conventional local anesthetics such as proparacaine inhibit voltage gated Na ion channels and are highly effective for the management of ocular pain in acute in office settings However these agents are short acting and toxic to the corneal surface which prevents their use beyond a few administrations The guanidinium toxins are a collection of naturally occurring small molecules that inhibit six of the nine isoforms of the mammalian voltage gated sodium channel NaV at low nanomolar concentrations In animal models of corneal tactile sensitivity topical administration of these agents has been shown to produce profound anesthesia with a duration of action that greatly exceeds that of proparacaine In addition these compounds appear to cause little to no toxicity to the corneal surface A significant liability of the natural compounds is poor permeability through the corneal epithelium which leads to high dosing requirements SiteOne has technology in place to prepare analogues of the natural guanidinium toxins by de novo chemical synthesis Using this technology we have generated a collection of novel guanidinium toxin derivatives with range of structural features and physicochemical properties By leveraging our collection of compounds and the ability to prepare novel optimized derivatives we aim to identify new chemical entities with improved pharmaceutical properties for the treatment of ocular pain PUBLIC HEALTH RELEVANCE Ocular pain is the single most common reason for a visit to an ophthalmologist Despite the high prevalence of this condition currently no drug is available to effectively manage it Existing local anesthetics such as proparacaine are toxic to the corneal surface and suitable only for in office administration We aim to develop a safe effective long acting topical therapy for ocular pain and discomfort which is suitable for patient self administration