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）， 这是一个日益严重的健康问题，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（T2 D）被认为是重要的病理生理学 因此，治疗T2 D和代谢性非酒精性脂肪性肝炎的新的治疗策略， 综合征也预期有益于NASH，这是一个显著未满足的需求。我们和其他人最近发现了一个 新型离子通道信号传导复合物SWELL 1/LRRC 8a（富含亮氨酸重复序列的蛋白质8a型）， 正调节脂肪细胞胰岛素-PI 3 K-AKT 2信号传导4，胰腺β细胞的胰岛素分泌， 全身葡萄糖稳态。此外，功能失调的脂肪细胞SWELL 1易患NAFLD， 肝细胞癌我们已经鉴定了一种小分子调节剂DCPIB（重命名为SN-401）， 结合SWELL 1-LRRC 8复合物的工具化合物，作为药理学伴侣， 增加SWELL 1表达和质膜运输。在体内，SN-401使葡萄糖耐量正常化 通过增加肥胖、T2 D小鼠模型的胰岛素敏感性和分泌。SN-401增加葡萄糖摄取 进入脂肪组织和心肌，抑制KKAy小鼠的肝脏葡萄糖产生，并保护 抗HFD喂养小鼠的肝脂肪变性和肝细胞气球样变。我们认为小分子 SWELL 1调节剂可能代表治疗代谢综合征的“一流”治疗方法 通过恢复跨多个器官系统的SWELL 1信号传导， 我们的总体目标是， 开发SN-401同系物（SN-40 X）的一个铅系列，从中选出一种铅和一种备用化合物 在2022年第一季度向FDA提交了研究性新药（IND）申请。 第1阶段目标： · AIM#1：SAR导向的SN-40 X体外优化和表征，以识别临床前先导化合物 结构. · AIM#2：完全体外吸收、分布、代谢、排泄、毒性和选择性 问题研究 第2阶段目标： · AIM#1：进行体内口服给药药代动力学和剂量范围发现毒性研究。 · AIM#2：进行临床前SN-40 X剂量反应和头对头功效研究， 奥贝胆酸（OCA）用于减缓NASH的进展、停止或逆转NASH ·目标#3：完成铅的固态表征、分析方法开发和验证 和备用化学、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.