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

摘要 在美国和其他发达国家，预期寿命的增加导致了与老龄化有关的疾病的增加。 膀胱功能障碍和相关的下尿路症状。衰老和糖尿病，以及许多 神经系统疾病，可导致膀胱活动不足（UAB），这可导致无效的排尿， 不适和心理痛苦，以及严重的并发症，如尿路感染。在 严重的情况下，UAB可导致自主排尿的丧失，并需要间歇性膀胱导管插入术， 这与健康问题的发生率增加有关，主要是反复的尿路 感染、败血症、尿道创伤和住院治疗。因此，短效、有效、安全的产品 诱导“按需”排尿将为UAB的管理提供一个范式转变， 减少或消除对间歇性导管插入术的需要。 Dignify Therapeutics正在开发一种新的药物治疗方法，以提供一种“按需，快速起效， 持续时间，药物诱导，排尿治疗”对于那些谁不能自愿排尿。给药时 静脉（IV）或皮下（sc）给大鼠、犬和小型猪注射神经激肽2受体（NK 2 R） 激动剂DTI-100快速诱导膀胱排尿。然而，静脉注射对于每天多次的 UAB患者所需的剂量。因此，Dignify正在开发舌下，鼻内， 皮下制剂，我们的领导发展的候选人，DTI-100，并发现，发病（约2 分钟）和作用持续时间（约10分钟），而在我们的临床产品概况的目标范围内， 如果进一步减少起始时间将更方便使用（即，30秒）。类似地第 作用持续时间的减少（即，3分钟）将减少任何残余的紧迫感，或 其他可能的副作用。此外，由于DTI-100尚未在人体中进行测试， 非天然氨基酸，Dignify也将检查仅含有天然氨基酸的化合物， DTI-100临床研究期间出现的任何非预期安全性问题。 在具体目标1中，将合成11种策略性选择的DTI-100结构类似物。 随后，将筛选它们的物理化学性质以及它们的NK 2 R亲和力和选择性 使用体外技术。在具体目标2中，8种最有吸引力的药物的体内药代动力学特征 将使用“盒式”方法筛选化合物。在具体目标3中，两个最有吸引力的 将测试候选人产生膀胱收缩的功效。成功完成本 该项目将确定第二代NK 2 R激动剂，具有改善的PK特性，并且可能更好地 有效性和耐受性。

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.