Discovery of Novel Pharmaceutical Agents for Skeletal Muscle Atrophy

DESCRIPTION provided by applicant Skeletal muscle atrophy is a highly prevalent condition caused by advanced age muscle disuse chronic illness critical illness and malnutrition In addition to being very common muscle atrophy has serious consequences including weakness reduced activity and quality of life falls fractures extended hospitalizatio and rehabilitation nursing home placement and increased mortality in chronic disease patients and the elderly However despite its broad clinical impact muscle atrophy lacks a medical therapy and current therapeutic approaches physical rehabilitation nutritional optimization and treatment of underlying disease are often ineffective and or unfeasible Thus skeletal muscle atrophy represents an enormous unmet medical need A major goal of Emmyon Inc is to develop a medical therapy for skeletal muscle atrophy In our preliminary studies we discovered ursolic acid UA as a novel small molecule inhibitor of skeletal muscle atrophy A natural compound found in apple peel and other edible plant materials UA possesses a favorable safety profile and improves muscle function in both mice and humans However UA has limited potential as a pharmaceutical because composition of matter claims which are critical for pharmaceutical development are not possible for natural compounds Thus to translate UA into a medicine Emmyon initiated a medicinal chemistry program to discover UA derivatives that enable composition of matter claims and also possess improved pharmacologic characteristics relative to native UA Through these efforts Emmyon has generated and tested a series of UA derivatives and discovered two novel derivatives EMMY and EMMY that significantly increase muscle strength when administered orally to young adult mice that lack muscle atrophy Furthermore our data suggest that EMMY and EMMY may be more potent than native UA In this phase I SBIR study Emmyon will determine if EMMY and EMMY reduce muscle atrophy In the proposed studies we will determine the feasibility of EMMY and EMMY as therapies for muscle atrophy induced by two distinct causes limb immobilization and aging EMMY and EMMY will orally administered to mice with immobilization induced muscle atrophy and mice with age related muscle atrophy sarcopenia Both UA derivatives will be directly compared to native UA which is known to reduce muscle atrophy following limb immobilization and during aging Compound efficacy will be determined by assessing grip strength specific force muscle mass muscle fiber size and molecular atrophy mediators Our goal is to identify at least one UA derivative that reduces muscle atrophy in both mouse models In Phase II studies Emmyon will carry the most promising UA derivative forward into pharmacokinetic and toxicology studies in rats and dogs and then an IND application Depending on the results of these studies the initial clinical study would be geared towards FDA approval for the treatment of disuse muscle atrophy and or age related muscle atrophy PUBLIC HEALTH RELEVANCE Skeletal muscle atrophy is a widespread and serious medical problem but lacks a medical therapy In this phase I SBIR study Emmyon Inc will generate new chemical compounds and test them in mice to determine if these compounds reduce muscle atrophy Effective compounds will represent promising potential medicines for skeletal muscle atrophy and will be carried towards human patients in phase II studies