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

使用功能性细胞收缩性筛选发现逼尿肌收缩的小分子增强剂作为膀胱活动不足的治疗候选物

• 批准号: 10326193
• 负责人: Ivan Pushkarsky
• 金额: $ 35.25万
• 依托单位: FORCYTE BIOTECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326193
• 关键词: Affect; Back; Biological Assay; Bladder; Catheterization; Catheters; Cells; Chemicals; Chemosensitization; Chronic Disease; Chronic Kidney Failure; Collection; Development Plans; Devices; Disease; Dose; Enhancers; Female; Goals; Human; Impairment; Indwelling Catheter; Letters; Libraries; Manuals; Methods; Muscle; Muscle Contraction; Oral; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Program Development; Property; Prostatic Urethra; Recommendation; Reporting; Research; Residual state; Resistance; Smooth Muscle; Smooth Muscle Myocytes; Specificity; Structure; Structure-Activity Relationship; Testing; Therapeutic; Time; Tissues; Triage; Urethra; Urinary Retention; Urine; Work; analog; base; cell type; cellular targeting; detrusor underactivity; drug development; functional genomics; high throughput screening; in silico; in vivo; lead optimization; male; multiplex assay; novel; patient population; pediatric patients; pressure; programs; response; scale up; screening; small molecule; therapeutic candidate; therapeutic development; urinary bladder neck; virtual

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.

膀胱活动不足(UAB) /逼尿肌活动不足（DU），是一种慢性疾病引起的