Discovery of tissue-selective, nonhypercalcemic VDR modulators for RA treatment

发现用于 RA 治疗的组织选择性、非高钙血症 VDR 调节剂

• 批准号: 8511162
• 负责人: WEI LI
• 金额: $ 15.94万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511162
• 关键词: 25-hydroxycholecalciferol-24-hydroxylase; Adrenal Cortex Hormones; Adverse effects; Aging; Agonist; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Bacteria; Biological; Blood; Caco-2 Cells; Cells; Cessation of life; Cholecalciferol; Chronic Disease; Collagen Arthritis; Disease remission; Disease-Modifying Second-Line Drugs; Dose; Drug Design; Drug usage; Future; Genes; Goals; Grant; Human; Hypercalcemia; Immune; Immune System Diseases; In Vitro; Inflammation; Intestines; Jurkat Cells; Lead; Life Expectancy; Literature; Methods; Modeling; Molecular Models; Nature; Non-Steroidal Anti-Inflammatory Agents; Nuclear Receptors; Organ failure; Population; Positioning Attribute; Preclinical Testing; Proteins; Receptor Activation; Research; Rheumatoid Arthritis; Secondary to; Selective Estrogen Receptor Modulators; Side; Skin; Small Intestines; Stereoisomer; Stroke; Structure-Activity Relationship; Symptoms; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Transcriptional Activation; Translating; Ulcer; Virus Diseases; Vitamin D; Vitamin D3 Receptor; Woman; analog; base; calcium absorption; design; drug development; effective therapy; high reward; high risk; improved; in vitro testing; in vivo; indexing; inflammatory marker; molecular modeling; novel; public health relevance; scaffold; selective androgen receptor modulator; selective expression; small molecule; success; viral leukemia

DESCRIPTION (provided by applicant): An estimated 1.3 million people in the US, especially women, suffer from rheumatoid arthritis (RA). Currently NSAIDs are used to relieve symptoms, and disease-modifying antirheumatic drugs (DMARDs) are used to produce remissions. However, these treatments are not satisfactory, prohibitively expensive (for protein based DMARDs), and often associated with potentially severe side effects. Biological understanding of the underline immune nature of RA accumulated in the last two decades have provided promises in using novel small molecules for better treatment of RA. We recently discovered that a novel class of vitamin D3 (VD3) metabolites, 20S-hydroxyvitamin D3 (20S(OH)D3), is highly efficacious against RA in vivo without resulting hypercalcemia or other detectable toxicities, even at very high doses. In this exploratory grant, we propose to test our overall hypothesis that the observed separation in strong efficacy against RA and the absence of hypercalcemia provided by this unique 20-hydroxy scaffold is due to the selective transcriptional activation of VDR in immune cells compared to intestine cells. This tissue selectivity, rather than the absolute potency of VDR activation, holds a new paradigm for developing clinically useful VD3 modulators for improved RA treatment. We have recently developed stereospecific synthetic methods to make new analogs. Some of these analogs show very promising anti-inflammation activities, at least comparable to that of 20S(OH)D3. Clearly there is room for further structural optimization based on 20S(OH)D3. Therefore, our objective is to develop several orally active, highly tissue-selective, VDR modulators based on this unique 20-hydroxyscaffold. Our specific aims are: (1) To test the hypothesis that the anti-inflammatory potency of 20S(OH)D3 can be further optimized with rational drug design. We will screen newly synthesized analogs against established markers for inflammation and use the structure-activity relationships (SAR) to guide iterative optimization for their anti-inflammatory activity. (2) To tst the hypothesis that the mechanism of action of the optimized highly active 20(OH)D3 analogs will selectively activate VDR in immune cells compared to intestine cells and that the in vitro selectivity observed will translate to in vivo efficacy for RA. We will test the hypotheses that (a they will activate VDR differentially in immune cells compared to intestine cells; (b) they will induce selective expression of key VDR- responsive genes in immune cells compared to intestine cells; (c) they will suppress RA efficiently without hypercalcemia using the well-established collagen induced arthritis (CIA) model. Our long term goal for this research is to develop novel classes of highly tissue-selective VDR modulators for immune cells compared to the intestine cells. Success in developing such agents will not only have high impact for RA, but will also have significant impact in treating many other autoimmune diseases.

描述（由申请人提供）：估计美国有 130 万人，尤其是女性，患有类风湿性关节炎 (RA)。目前，非甾体抗炎药用于缓解症状，缓解疾病抗风湿药 (DMARD) 用于缓解症状。然而，这些治疗方法并不令人满意，价格昂贵（对于基于蛋白质的 DMARD），并且常常伴有潜在的严重副作用。过去二十年积累的对 RA 免疫本质的生物学认识为使用新型小分子更好地治疗 RA 提供了希望。 我们最近发现一类新型维生素 D3 (VD3) 代谢物 20S-羟基维生素 D3 (20S(OH)D3) 在体内对 RA 非常有效，即使在非常高的剂量下也不会导致高钙血症或其他可检测到的毒性。在这项探索性资助中，我们建议测试我们的总体假设，即这种独特的 20-羟基支架所观察到的对 RA 的强大功效的分离以及不存在高钙血症是由于与肠细胞相比，免疫细胞中 VDR 的选择性转录激活。这种组织选择性，而不是 VDR 激活的绝对效力为开发临床上有用的 VD3 调节剂以改善 RA 治疗提供了新范例。我们最近开发了立体定向合成方法来制造新的类似物。其中一些类似物显示出非常有前途的抗炎活性，至少与 20S(OH)D3 相当。显然基于20S(OH)D3还有进一步结构优化的空间。因此，我们的目标是基于这种独特的 20-羟基支架开发几种口服活性、高度组织选择性的 VDR 调节剂。 我们的具体目标是：（1）检验20S(OH)D3的抗炎功效可以通过合理的药物设计进一步优化的假设。我们将针对已建立的炎症标志物筛选新合成的类似物，并使用构效关系（SAR）来指导其抗炎活性的迭代优化。 (2) 验证以下假设：与肠细胞相比，优化的高活性 20(OH)D3 类似物的作用机制将选择性激活免疫细胞中的 VDR，并且观察到的体外选择性将转化为体内对 RA 的功效。我们将测试以下假设：(a) 与肠道细胞相比，它们将在免疫细胞中差异性地激活 VDR；(b) 与肠道细胞相比，它们将诱导免疫细胞中关键 VDR 响应基因的选择性表达；(c) 它们将抑制 RA使用成熟的胶原诱导关节炎 (CIA) 模型，我们的长期目标是为免疫细胞开发新型的高度组织选择性的 VDR 调节剂，与肠道细胞相比，成功开发此类药物将有助于实现这一目标。不仅拥有高对 RA 的影响，但也将对治疗许多其他自身免疫性疾病产生重大影响。