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相关的人口增加 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 神经疾病会导致膀胱活动不足(UAB)，这可能会导致排尿效率低下， 不适和精神痛苦，以及严重的并发症，如尿路感染。在……里面 严重的情况下，UAB会导致自主排尿丧失，需要间歇性导尿， 这与健康问题的发生率增加有关，主要是重复的尿路 感染、败血症、尿路损伤和住院。因此，一个短效、有效、安全的产品 这种“按需”作废的做法将使UAB的管理模式发生转变，并可能 减少或消除间歇性导尿的需要。 Diguify Treateutics正在开发一种新的药物治疗方法，以提供“按需、起效快、时间短”的 持续时间、药物诱导、排尿治疗“，适用于那些不能自愿排尿的人。当给药时 大鼠、狗和小型猪静脉注射或皮下注射神经激肽2受体(NK2R) 激动剂DTI-100可迅速诱导膀胱排尿。然而，静脉注射对于每天多次注射是不切实际的 UAB患者所需剂量。因此，尊严正在发展为舌下、鼻内和 我们的主要开发候选药物DTI-100的皮下配方，并发现onsets(约2 最小)和持续时间(约10分钟)，而在我们的临床产品配置文件的目标范围内， 如果起效时间进一步缩短(即30秒)，使用起来会更方便。类似地，一个 缩短行动持续时间(即3分钟)将减少任何残留的紧迫感或 其他可能的副作用。此外，由于DTI-100尚未在人体内进行测试，因此含有 非天然氨基酸，尊严也将检查只含有天然氨基酸的化合物，以防 在DTI-100的临床研究中出现任何意想不到的安全问题。 在具体目标1中，将合成11个经过战略选择的DTI-100结构类似物。 随后，将对它们的物理化学性质以及它们的NK2R亲和力和选择性进行筛选 使用体外技术。在特定目标2中，8种最具吸引力的体内药动学曲线 化合物将使用“盒式”方法进行筛选。在具体目标3中，最具吸引力的2个 考生将接受导致膀胱收缩的有效性测试。成功完成这项工作 该项目将确定第二代NK2R激动剂，具有改进的PK特性，可能还会更好 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.