Novel, Potent and Metabolically Stable Oxytocin Analogues to Treat Obesity

The goal of this project is to develop novel oxytocinOXTanalogues with improved safety and efficacy vsnative OXT for the treatment of obesity and related metabolic disordersObesity is an increasing health care burden in the US andeven though it is recognized as a significant risk factor for developing cardiovascular disease and typediabetesthere has been limited progress in developing safe and effective methods for reducing body weightDiet and exercise have proven ineffective for most patients while eligibility criteria for bariatric surgery limits itsuse to only the most obese individualsThe use of pharmacotherapy to treat obesity has also been challenging due to limited efficacy and significant safety concernsincluding serious behavioral and cardiovascular side effectswhich have limited their clinical useOXT is a downstream target of the adiposity signal leptinOXT is an attractive therapeutic target to treat obesity in humans because it reduces body weight in diet induced obeseDIOrodents even in the face of an impaired ability of leptin to reduce food intakeMoreoverwe recently translated these effects to DIO nonhuman primates and determined that OXT induces weight loss via combined effects of reducing food intake and increasing energy expenditureNumerous studies in animal models and humans have demonstrated that activation of the OXT receptorOXTReffectively reduces body weight through multiple mechanismsincluding increased satietyenergy expenditureand improved lipid metabolismNeverthelessOXT and its published analogues exhibit poor metabolic stability resulting in short plasma half lifepotential to induce off target toxicity via vasopressin family of receptorsand sub optimal OXTR agonistic activityWith the proposed studieswe aim to target the OXT signaling pathway using novel selectivepotent and metabolically stable OXT analogues with the goal to develop a pharmacotherapy for safe and effective obesity interventionWe already have developed a series of novel molecules with significantly improved metabolic stability and comparable or better activity at OXTRPreliminary in vivo studies support the significant potential of these analogues as weight loss agentsWe now propose to further characterize our analogues in vitro potency against OXTRi eactivation of GqGi and Goand selectivity versus vasopressin V a b and Vreceptors in cell based reporter assaysAimPromising agents will be evaluated for their minimum effective and maximum tolerated doses in SpragueDawley rats as well as their in vivo pharmacokinetic propertiesOne champion OXT analogue will be further evaluated in DIO rats during longerd treatment on changes of body weightfood intakeinflammatory and metabolic parametersand measures of energy homeostasisAimAfter completion of these studiesseveral lead molecules will be evaluated for detailed pharmacokineticsbiodistributioni eCNS penetrationpreclinical toxicologyand long term efficacyDIO and genetic obesity modelsin a phase II STTR grant that will position us to conduct an Investigational New Drug application and prepare for clinical trials This proposal is focused on the development of novel potentselectivemetabolically stable and safe agents as improvements of the native hormone oxytocinThese agents reduce food consumption and weight gain in rodent animal models with greater efficiency than the native hormoneMost promising candidates will be evaluated in multiple lean and obese rat models in order to understand their efficacymode of action and safety profileand to identify molecules that could potentially proceed toward clinical testing as weight loss agents in the future