Identification of RORg drug candidates for the treatment of NASH

鉴定治疗 NASH 的 RORg 候选药物

• 批准号: 9346642
• 负责人: Jim Zapf
• 金额: $ 15.65万
• 依托单位: VISIONARY PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-09 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9346642
• 关键词: Agonist; American; Attenuated; Biological Availability; Cells; Cessation of life; Cirrhosis; Clinic; Data; Development; Diet; Disease; Drug Kinetics; Epidemic; Etiology; Excretory function; Fibrosis; Genetic; Genetic Models; Hepatic Stellate Cell; Hepatocyte; High Fat Diet; Human; In Vitro; Interleukin-17; Kupffer Cells; Liver Fibrosis; Liver diseases; Mediator of activation protein; Metabolism; Mus; Nuclear Receptors; Obesity; Oral; Orphan; Patients; Peripheral Blood Lymphocyte; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Pre-Clinical Model; Primary carcinoma of the liver cells; Property; Proteins; Retinoid Receptor; Series; Signal Transduction; Small Business Innovation Research Grant; Steatohepatitis; Structure; Structure-Activity Relationship; Testing; Therapeutic; Transgenic Mice; Translating; Treatment Efficacy; absorption; base; cytokine; design; diabetic cardiomyopathy; drug candidate; drug discovery; fast food; improved outcome; mortality; mouse model; non-alcoholic fatty liver; non-drug; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; novel therapeutics; orphan nuclear receptor ROR-gamma; receptor; standard of care; targeted treatment

ABSTRACT: Significance: An epidemic proportion of Americans (approximately 75-100 million) suffer from obesity and nonalcoholic fatty liver disease, a spectrum of progressive liver disease that include steatosis, non- alcoholic steatohepatitis (NASH), fibrosis and, eventually, cirrhosis, and hepatocellular carcinoma (HCC). There is no standard of care pharmacotherapy for NASH. Therefore, new therapeutic approaches are urgently needed. IL-17 is a critical mediator of liver fibrosis of different etiologies including NASH. We have recently demonstrated that blocking of IL-17 signaling in IL-17RA-/- mice attenuated development of cholestatic and toxic liver fibrosis by 75%, suggesting that IL-17 may serve as a novel target for anti-NASH therapy. Expression of IL-17 cytokine is regulated by the nuclear receptor retinoid-related orphan receptor γt (RORγt), which belongs to a “druggable” class of proteins that are targeted by 15% of prescribed drugs. Hypothesis: We hypothesize that a new class of RORγ inverse agonists identified in our labs will most effectively attenuate the development of NASH (steatohepatitis and fibrosis) via inhibition of IL-17 signaling. Preliminary Data: Genetic deletion of IL-17 signaling attenuates NASH-induced liver fibrosis in two mouse models of NASH: the high fat diet induced-, and Mup-uPA genetic- models of NASH. On the drug discovery front, we identified 3 new classes of RORγ inverse agonists, which based on initial medicinal chemistry studies on one series, demonstrate structure activity relationships (SAR), potency against IL-17 in hPBMCs (IC50 = ~200nM), oral bioavailability (70%), and effective inhibition of cholestatic and toxic fibrosis in mice. Specific Aims: We will prove the concept that RORγ inverse agonist compounds are therapeutically efficacious in preclinical models of NASH thus justifying the effort to develop these as drugs for NASH patients (Phase II SBIR). Aim 1. We will use medicinal chemistry/structure based design to optimize RORγ potency, selectivity against other nuclear receptors, and in vitro absorption, distribution, metabolism, and excretion (ADME) properties of an RORγ inverse agonist series. Aim 2, we will test if RORγ inverse agonists from Aim 1 have anti-IL-17 activity in primary human Peripheral Blood Lymphocytes (PBLs), primary human Kupffer cells, Hepatic Stellate Cells and hepatocytes (identified as IL-17 target cells), and use pharmacokinetic studies to select compounds with an effective pharmacological exposure in mice. Aim 3. We will test if optimized RORγ inverse agonists are well tolerated in mice and are therapeutically effective in two preclinical models of NASH: the “fast food diet” (FFD) and Mup-uPA transgenic mice. These studies will establish RORγ inverse agonists as a new therapy for NASH. Further, the patentable and drug-like leads produce herein could rapidly be translated to the clinic and developed as a targeted therapy for NASH patients.

摘要：重要性：美国人（约7500万至1亿人）患有流行病， 肥胖和非酒精性脂肪肝，一系列进行性肝病，包括脂肪变性，非酒精性脂肪肝， 酒精性脂肪性肝炎（NASH）、纤维化以及最终的肝硬化和肝细胞癌（HCC）。 NASH没有标准的药物治疗。因此，迫切需要新的治疗方法。 needed. IL-17是包括NASH在内的不同病因的肝纤维化的关键介质。我们最近 表明阻断IL-17 RA-/-小鼠中的IL-17信号传导可减弱胆汁淤积的发展， 中毒性肝纤维化减少75%，表明IL-17可作为抗NASH治疗的新靶点。 IL-17细胞因子的表达受核受体维甲酸相关孤儿受体γt（RORγt）调节， 它属于一种“可药物化”的蛋白质，15%的处方药都是以这种蛋白质为目标的。假设： 我们假设在我们的实验室中发现的一类新的RORγ反向激动剂将最有效地减弱 通过抑制IL-17信号传导导致NASH（脂肪性肝炎和纤维化）的发展。初步数据： IL-17信号转导的基因缺失在两种NASH小鼠模型中减弱NASH诱导的肝纤维化： 高脂饮食诱导的NASH模型和Mup-uPA遗传模型。在药物发现方面，我们确定了3个 RORγ反向激动剂的新类别，其基于对一个系列的初始药物化学研究， 证明构效关系（SAR），在hPBMC中对IL-17的效力（IC 50 = ~ 200 nM），口服 生物利用度（70%），并在小鼠中有效抑制胆汁淤积性和毒性纤维化。具体目标：我们将 证明RORγ反向激动剂化合物在临床前模型中具有治疗有效性的概念 因此证明了开发这些药物作为NASH患者药物的努力（II期SBIR）。目标1.我们将 使用基于药物化学/结构的设计来优化RORγ效力、对其他核的选择性 受体，以及RORγ的体外吸收、分布、代谢和排泄（ADME）特性 反向激动剂系列。目的2，我们将测试来自目的1的RORγ反向激动剂是否具有抗IL-17活性。 原代人外周血淋巴细胞（PBL）、原代人枯否细胞、肝星状细胞和 肝细胞（鉴定为IL-17靶细胞），并使用药代动力学研究来选择具有 有效的药理学暴露。目标3。我们将测试优化的RORγ反向激动剂是否能够很好地 在小鼠中耐受，并且在NASH的两种临床前模型中治疗有效：“快餐饮食”（FFD） 和Mup-uPA转基因小鼠。这些研究将确立RORγ反向激动剂作为一种新的治疗方法， 纳什此外，本文产生的可专利的和药物样的先导物可以迅速转化为临床， 作为NASH患者的靶向治疗而开发。