Optimizing SWELL1 modulators to treat non-alcoholic steatohepatitis

非酒精性脂肪肝(NAFL)及其进展为晚期非酒精性脂肪性肝炎(NASH) 人们对健康的担忧日益加剧，2015年有8310万美国人受到影响，预计将达到1.009亿 到2030年。代谢综合征和2型糖尿病(T2D)被认为是重要的病理生理学 因此，NAFL-NASH进展的贡献者是治疗T2D和代谢的新治疗策略 预计综合症也将使NASH受益，这是一种重要的未得到满足的需求。我们和其他人最近发现了一个 新的离子通道信号复合体SWELL1/LRRC8a(富含亮氨酸重复序列包含8a蛋白) 正向调节脂肪细胞胰岛素-PI3K-AKT2信号，胰腺β细胞的胰岛素分泌，以及 全身血糖动态平衡。此外，功能失调的脂肪细胞SWELL1易患NAFLD和 肝细胞癌。我们鉴定了一种小分子调节剂DCPIB(更名为SN-401)，它是一种 结合SWELL1-LRRC8复合体并作为药物伴侣的工具化合物 增强SWELL1的表达和质膜转运。在体内，SN-401可使糖耐量正常化 通过增加肥胖T2D小鼠模型的胰岛素敏感性和分泌。SN-401可增加葡萄糖摄取 进入脂肪组织和心肌，抑制KKAy小鼠肝脏葡萄糖的产生，并保护 抗高脂饲料喂养小鼠的肝脏脂肪变性和肝细胞肿胀。我们提出了小分子 SWELL1调节剂可能是治疗代谢综合征的一种“一流”治疗方法 并通过恢复跨多个器官系统的SWELL1信号来关联NASH T2D功能障碍并导致NASH的复杂病理生理机制我们的总体目标是 开发一系列SN-401同系物(SN-40X)，从中选择一种先导化合物和一种后备化合物 2022年第一季度向FDA提交研究新药(IND)申请，用于人体。 第一阶段的目标是： ·目标1：合成孔径雷达引导的SN-40X体外优化和表征，以确定临床前导联 结构。 ·目标2：完全体外吸收、分布、代谢、排泄、毒性和选择性 学习。 第二阶段的目标是： ·目的1：进行体内口服给药药代动力学和剂量范围毒性研究。 ·目标2：进行临床前SN-40X剂量反应和面对面疗效研究 用于减缓、阻止或逆转NASH进展的乙酰胆酸(OCA) ·目标3：铅的完整固态表征、分析方法开发和验证 以及备用化学、制造和控制(CMC)途径。

Non-alcoholic fatty liver (NAFL) and its progression to advanced stage non-alcoholic steatohepatitis (NASH) is a growing health concern, with 83.1 million Americans affected in 2015, and projections to reach 100.9 million by 2030. Metabolic syndrome and Type 2 diabetes (T2D) are considered significant pathophysiological contributors to NAFL-NASH progression, therefore, novel therapeutic strategies to treat T2D and metabolic syndrome are also expected to benefit NASH, a significant unmet need. We, and others, recently identified a novel ion channel signaling complex, SWELL1/LRRC8a (Leucine rich repeat containing protein type 8a) that positively regulates adipocyte insulin-PI3K-AKT2 signaling4, insulin secretion from pancreatic β-cells, and systemic glucose homeostasis. Moreover, dysfunctional adipocyte SWELL1 predisposes to NAFLD and hepatocellular carcinoma. We have identified a small molecule modulator, DCPIB (renamed SN-401), as a tool compound that binds the SWELL1-LRRC8 complex and functions as a pharmacological chaperone to augment SWELL1 expression and plasma membrane trafficking. In vivo, SN-401 normalizes glucose tolerance by increasing insulin sensitivity and secretion in obese, T2D mouse models. SN-401 augments glucose uptake into adipose tissue and myocardium, suppresses hepatic glucose production in KKAy mice, and protects against hepatic steatosis and hepatocyte ballooning in HFD fed mice. We propose that small molecule SWELL1 modulators may represent a “first-in-class” therapeutic approach to treat metabolic syndrome and associated NASH by restoring SWELL1 signaling across multiple organ systems that are dysfunctional in T2D and contribute to the complex pathophysiology of NASH Our overall objective is to develop a lead series of SN-401 congeners (SN-40X) from which to select one lead and one back-up compound to take into humans, with submission of an Investigational New Drug (IND) application to the FDA in Q1 of 2022. Phase 1 AIMS: • AIM#1: SAR-directed SN-40X optimization and characterization in vitro to identify preclinical lead structures. • AIM#2: Complete in vitro absorption, distribution, metabolism, excretion, toxicity and selectivity studies. Phase 2 Aims: • AIM#1: Perform in vivo oral dosing pharmacokinetics and dose-range finding toxicity studies. • AIM#2: Perform pre-clinical SN-40X dose-response and head-to-head efficacy studies against obeticholic acid (OCA) for slowing progression of, halting, or reversing NASH • AIM#3: Complete solid-state characterization, analytical methods development & validation for lead and backup chemistry, manufacturing, and controls (CMC) pathways.