Small molecule enhancers of detrusor contraction discovered using a functional cell contractility screen as therapeutic candidates for underactive bladder

膀胱活动不足(UAB)/逼尿肌活动不足(DU)，是一种慢性疾病，由 膀胱的收缩功能在其强度和/或持续时间上受损，导致延长 膀胱排尿或无法在正常时间范围内实现膀胱的完全排尿。 如果不进行治疗，尿液滞留和回流的增加将导致严重的和不可逆转的 膀胱损伤和慢性肾脏疾病。UAB中没有可用的口服药物 完全有效和插管通常是治疗的标准建议 UAB引起的尿潴留，甚至在患有特发性UAB的儿童患者中也是如此。这 要求患者携带留置导管和外部收集装置或更多 通常，每天要自我导尿四到六次，需要手动引导导尿管。 通过一个人的尿路进入膀胱。Forcell进行了有史以来第一次高通量筛选 关于11500个小分子的膀胱细胞收缩能力，确定了两个有希望的命中簇。使用 评估这些点击的潜力，以启动不活跃的膀胱治疗的目标 发展计划，目标1将通过实验和电子手段确定SAR 2将专注于使用虚拟手段扩大命中率，以产生更多的射门机会，而Aim 3将 建立有效分子的配位性质以指导提名3-5个线索 领导第二阶段的优化研究。

Underactive bladder (UAB) / detrusor underactivity (DU), is a chronic disorder arising from impaired contractile function of the bladder in its strength and/or duration, causing prolonged bladder voiding or inability to achieve complete voiding of the bladder at normal time scales. Without treatment, increased urinary retention and back-up will lead to severe and irreversible bladder damage and chronic kidney disease. No available oral medication used in the UAB is completely effective and catherization is often the standard recommendation for managing urinary retention resulting from UAB, even in pediatric patients with idiopathic UAB. This requires the patient either to carry an indwelling catheter and external collection device or more commonly, to self-catheterize four and six times daily, a involving manually guiding a catheter through one’s urethra to the bladder. Forcyte performed the first ever high-throughput screen on bladder cell contractility of 11500 small molecules, identifying two promising hit clusters. With the goal of evaluating the potential of these hits to launch underactive bladder therapeutic development programs, Aim 1 will determine SAR through experimental and in silico means, Aim 2 will focus on hit expansion using virtual means to generate more shots on goal, and aim 3 will establish the ADMET properties of potent molecules to guide nomination of 3-5 leads to advance to lead-optimization research in Phase 2.