Identification of an optimized NK2R agonist for 'on-demand' voiding

ABSTRACT In the US and other developed countries increased life expectancy has led to increases in aging related bladder dysfunction and associated lower urinary tract symptoms Aging and diabetes as well as many neurological conditions can result in underactive bladder UAB which can cause inefficient voiding discomfort and psychological distress as well as serious complications such as urinary tract infections In severe cases UAB can cause loss of voluntary urination and require intermittent bladder catheterization which is associated with increased incidence of health problems predominately repeated urinary tract infections sepsis urethral trauma and hospitalization Therefore a short acting effective and safe product that induces on demand voiding would provide a paradigm shift in the management of UAB and could reduce or eliminate the need for intermittent catheterization Dignify Therapeutics is developing a novel drug treatment to provide an on demand rapid onset short duration drug induced voiding therapy for those who cannot void voluntarily When administered intravenously IV or subcutaneously sc to rats dogs and minipigs the neurokinin receptor NK R agonist DTI rapidly induces bladder voiding However IV injection is impractical for the multiple daily dosing required by individuals with UAB Therefore Dignify is developing sublingual intranasal and subcutaneous formulations of our lead development candidate DTI and find that the onsets about min and durations about min of action while within the target range of our clinical product profile would be even more convenient to use if onset time were further reduced i e seconds Similarly a reduction in the duration of action i e minutes would reduce any residual sensations of urgency or other possible side effects In addition since DTI has not yet been tested in man and contains unnatural amino acids Dignify will also examine compounds that contain only natural amino acids in case any unexpected safety issues appear during clinical study of DTI In Specific Aim eleven strategically selected structural analogs of DTI will be synthesized Subsequently their physicochemical properties as well their NK R affinity and selectivity will be screened using in vitro techniques In Specific Aim the in vivo pharmacokinetic profiles of the most attractive compounds will be screened using a cassette approach In Specific Aim the most attractive candidates will be tested for efficacy in producing bladder contractions Successful completion of this project will identify a nd generation NK R agonist with improved PK properties and presumably better efficacy and tolerability PROJECT NARRATIVE The ultimate aim of this project is to provide to individuals with underactive bladder a novel pharmaceutical treatment that will produce efficient on demand voiding Underactive bladder can be embarrassing and uncomfortable and it is associated with serious complications such as urinary tract infections This grant will enable the identification of high priority candidates for a novel drug to provide on demand urination Success of our project will restore individual dignity improve daily quality of life and health and reduce associated health care costs for individuals who have diminished voluntary control of their bladder