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

摘要

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 2 receptor (NK2R) agonist DTI-100 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-100, and find that the onsets (about 2 min) and durations (about 10 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., 30 seconds). Similarly, a reduction in the duration of action (i.e., 3 minutes) would reduce any residual sensations of urgency or other possible side effects. In addition, since DTI-100 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-100. In Specific Aim 1, eleven strategically selected structural analogs of DTI-100 will be synthesized. Subsequently, their physicochemical properties, as well their NK2R affinity and selectivity, will be screened using in vitro techniques. In Specific Aim 2, the in vivo pharmacokinetic profiles of the 8 most attractive compounds will be screened using a “cassette” approach. In Specific Aim 3, the 2 most attractive candidates will be tested for efficacy in producing bladder contractions. Successful completion of this project will identify a 2nd generation NK2R agonist with improved PK properties, and presumably better efficacy and tolerability.