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

点击翻译按钮获取中文摘要

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.