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， 膀胱的收缩功能在其强度和/或持续时间方面受损，导致延长 膀胱排尿或不能在正常时间尺度上实现膀胱的完全排尿。 如果不治疗，尿潴留和备份增加将导致严重的和不可逆的 膀胱损伤和慢性肾病。UAB中没有可用的口服药物， 完全有效，插管通常是管理的标准建议 UAB导致的尿潴留，即使在患有特发性UAB的儿科患者中也是如此。这 需要患者携带留置导管和外部收集装置或更多 通常，每天自我导尿四次和六次，a涉及手动引导导管 通过尿道到达膀胱Forcyte进行了第一次高通量筛选 对11500个小分子的膀胱细胞收缩性的影响，鉴定了两个有希望的命中簇。与 目标是评估这些命中的潜力，推出膀胱活动不足的治疗， 目标1将通过实验和计算机模拟手段确定SAR， 2将专注于使用虚拟手段进行命中扩展，以产生更多的射门，而aim 3将 建立有效分子的ADMET特性，以指导3-5个先导化合物的提名， 在第二阶段领导优化研究。

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.